Hetereoaryl nitrile derivatives

ABSTRACT

The invention provides compounds of Formula (I) or a pharmaceutically acceptable salt or ester thereof wherein the symbols have meaning as defined, which are inhibitors of cathepsin K and find use pharmaceutically for treatment of diseases and medical conditions in which cathepsin K is implicated, e.g. various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumors.

This invention relates to inhibitors of cysteine proteases, inparticular to heteroaryl nitrile cathepsin K inhibitors and to theirpharmaceutical use for the treatment or prophylaxis of diseases ormedical conditions in which cathepsin K is implicated.

Cathepsin K is a member of the family of lysosomal cysteine cathepsinenzymes, e.g. cathepsins B, K, L and S, which are implicated in variousdisorders including inflammation, rheumatoid arthritis, osteoarthritis,osteoporosis, tumors (especially tumor invasion and tumor metastasis),coronary disease, atherosclerosis (including atherosclerotic plaquerupture and destabilization), autoimmune diseases, respiratory diseases,infectious diseases and immunologically mediated diseases (includingtransplant rejection).

Accordingly the present invention provides a compound of formula I, or apharmaceutically acceptable salt or ester thereof

In which

-   R is H, —R2, —OR2 or NR1R2,-   wherein R1 is H, lower alkyl or C₃ to C₁₀ cycloalkyl, and-   R2 is lower alkyl or C₃ to C₁₀ cycloalkyl, and-   wherein R1 and R2 are independently, optionally substituted by halo,    hydroxy, lower alkoxy, CN, NO₂, or optionally mono- or di-lower    alkyl substituted amino;-   X is ═N— or ═C(Z)-,-   wherein Z is H, —R4, —C≡C—CH₂—R5, C(P)=C(Q)—R3,    wherein-   P and Q independently are H, lower alkyl or aryl,-   R3 is aryl, aryl-lower alkyl, C₃-C₁₀cycloalkyl,    C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower    alkyl,-   wherein R3 is independently, optionally substituted by one or more    groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower    alkoxy, CN or NO₂, or optionally substituted (optionally mono- or    di-lower alkyl substituted amino, aryl, aryl-lower alkyl,    N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional    substitution comprises from 1 to 3 substituents selected from halo,    hydroxy, lower alkoxy, CN, NO₂, or optionally mono- or di-lower    alkyl substituted amino)),-   R4 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl,    C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl or    heterocyclyl-lower alkyl, and wherein-   R5 is aryl, aryl-lower alkyl, aryloxy, aroyl or N-heterocyclyl as    defined above, and wherein R5 is optionally substituted by R7 which    represents from 1 to 5 substitutents selected from halo, hydroxy,    CN, NO₂ or oxo, or optionally substituted (lower-alkoxy,    lower-alkyl, aryl, aryloxy, aroyl, lower-alkylsulphonyl,    arylsulphonyl, optionally mono- or di-lower alkyl substituted amino,    or N-heterocyclyl, or N-heterocyclyl-lower alkyl, wherein    N-heterocyclyl denotes a saturated, partially unsaturated or    aromatic nitrogen containing heterocyclic moiety attached via a    nitrogen atom thereof having from 3 to 8 ring atoms optionally    containing a further 1, 2 or 3 heteroatoms selected from N, NR6, O,    S, S(O) or S(O)₂ wherein R6 is H or optionally substituted (lower    alkyl, carboxy, acyl (including both lower alkyl acyl, e.g. formyl,    acetyl or propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O)    or S(O)₂), and wherein the N-heterocyclyl is optionally fused in a    bicyclic structure, e.g. with a benzene or pyridine ring, and    wherein the N-heterocyclyl is optionally linked in a spiro structure    with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the    heterocyclic ring has from 3 to 10 ring members and contains from 1    to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O)₂ wherein    R6 is as defined above), and-   wherein heterocyclyl denotes a ring having from 3 to 10 ring members    and containing from 1 to 3 heteroatoms selected from N, NR6, O, S,    S(O) or S(O)₂ wherein R6 is as defined above), and and-   wherein R7 is optionally substituted by from 1 to 3 substitutents    selected from halo, hydroxy, optionally mono- or di- lower-alkyl    substituted amino, lower-alkyl carbonyl, lower-alkoxy or    lower-alkylamido;-   Y is -NR8R9,    wherein-   R8 is H, or optionally substituted (lower alkyl, aryl, aryl-lower    alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl    or heterocyclyl-lower alkyl),-   wherein R8 is optionally substituted by R10 which represents from 1    to 4 substitutents selected from halo, hydroxy, CN, NO₂, —O—C(O)—,    optionally substituted (lower-alkyl, C₃-C₁₀cycloalkyl, lower-alkoxy,    lower-alkenyl, lower-alkynyl, optionally mono- or di-lower    alkyl-substituted amino or N-heterocyclyl (as defined above),-   wherein R10 is optionally substituted by R11 which represents from 1    to 4 substituents selected from halo, hydroxy, CN, NO₂, oxo,    optionally substituted (optionally mono- or di-lower    alkyl-substituted amino, lower alkyl, optionally-lower alkyl    substituted COOH, sulphinyl, sulphonyl, or N-heterocyclyl (as    defined above))-   wherein R11 is optionally substituted by R12 which represents from 1    to 4 substituents selected from halo, hydroxy, CN, NO₂, oxo, hydroxy    lower alkyl, C₃-C₁₀cycloalkyl, optionally lower alkyl-substituted    carboxy, hydroximine, or N-heterocyclyl as defined above, and    wherein-   R9 is independently H, or optionally substituted (lower alkyl, aryl,    aryl-lower alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-lower alkyl,    heterocyclyl or heterocyclyl-lower alkyl), and-   wherein R9 is optionally substituted by halo, hydroxy, oxo, lower    alkoxy, CN, NO₂, or optionally mono- or di-lower alkyl substituted    amino;-   or Z and Y together with the carbon atoms to which they are attached    are joined to provide a compound of formula I selected from,    wherein-   R is as defined above;-   R15 is lower-alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-lower alkyl,    NR2OR21-lower alkyl-, where-   T is —O— or a direct bond;-   R16 is NR2OR21-lower alkyl- or R4, both as defined above,    wherein-   R20 is H, optionally substituted (lower alkyl, aryl,    C₃-C₁₀cycloalkyl, lower alkoxy lower alkyl C₃-C₁₀cycloalkyl-lower    alkyl or aryl lower alkyl),-   R21 is optionally substituted (lower alkyl, aryl, C₃-C₁₀cycloalkyl,    lower alkoxy lower alkyl, C₃-C₁₀cycloalkyl-lower alkyl or aryl-lower    alkyl), or-   R20 and R21 form an N-heterocyclyl ring as hereinbefore defined,-   and wherein R20 or R21 are independently optionally substituted by    R23 which which represents from 1 to 3 substitutents selected from    halo, hydroxy, CN, NO₂, oxo, optionally mono- or di-lower alkyl    substituted amino, or optionally substituted (lower-alkoxy,    lower-alkyl, lower alkoxy carbonyl, aryl, aryl-lower alkyl,    aryl-lower alkenyl, aryloxy, aroyl, alkylsulphonyl, arylsulphonyl or    N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein N-heterocyclyl    is as defined above)); and-   A is —CH═ or —C(O)—, B is —C═ or —N—, D is —CH═ or —C(O)— and E is    —CH═ or —N(R1) (where R1 is as defined above).

Above and elsewhere in the present description the following terms havethe following meanings.

Halo or halogen denote I Br, Cl or F.

The term “lower” referred to above and hereinafter in connection withorganic radicals or compounds respectively defines such as branched orunbranched with up to and including 7, preferably up to and including 5and advantageously one, two or three carbon atoms. A lower alkyl groupis branched or unbranched and contains 1 to 7 carbon atoms, preferably1-5 carbon atoms. Lower alkyl represents; for example, methyl, ethyl,propyl, butyl, isopropyl isobutyl, tertiary butyl or neopentyl(2,2-dimethylpropyl).

Halo-substituted lower alkyl is C₁-C₇1lower alkyl substituted by up to 6halo atoms. A lower alkoxy group is branched or unbranched and contains1 to 7 carbon atoms, preferably 1-4 carbon atoms. Lower alkoxyrepresents for example methoxy, ethoxy, propoxy, butoxy, isopropoxy,isobutoxy or tertiary butoxy.

A lower alkene, alkenyl or alkenyloxy group is branched or unbranchedand contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms andcontains at least one carbon-carbon double bond. Lower alkene loweralkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl,allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalentsthereof.

A lower alkyne, alkynyl or alkynyloxy group is branched or unbranchedand contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms andcontains at least one carbon-carbon triple bond. Lower alkyne or alkynylrepresents for example ethynyl, prop-1-ynyl, propargyl, butynyl,isopropynyl or isobutynyl and the oxy equivalents thereof In the presentdescription, oxygen containing substituents, e.g. alkoxy, alkenyloxy,alkynyloxy, carbonyl, etc. encompass their sulphur containinghomologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy,thiocarbonyl, sulphone, sulphoxide etc.

Aryl represents carbocyclic or heterocyclic aryl.

Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, forexample phenyl or phenyl mono-, di- or tri-substituted by one, two orthree radicals selected from lower alkyl, lower alkoxy, aryl, hydroxy,halogen, cyano, trifluoromethyl, lower alkylenedioxy andoxy-C₂-C₃-alkylene and other substituents, for instance as described inthe examples; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Loweralkylenedioxy is a divalent substituent attached to two adjacent carbonatoms of phenyl, e.g. methylenedioxy or ethylenedioxy.Oxy-C₂-C₃-alkylene is also a divalent substituent attached to twoadjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. Anexample for oxy-C₂-C₃-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl optionallysubstituted, for instance, as described in the examples, e.g. mono- ordisubstituted by lower alkoxy, phenyl, halogen, lower alkyl ortrifluoromethyl.

Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, forexample pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,pyrazolyl, imidazolyl, thienyl, or any said radical substituted,especially mono- or di-substituted as defined above.

Preferably, heterocyclic aryl is pyridyl, indolyl, quinolinyl, pyrrolyl,thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl,thienyl, or any said radical substituted, especially mono- ordi-substituted as defined above.

Cycloalkyl represents a saturated cyclic hydrocarbon optionallysubstituted by lower alkyl which contains 3 to 10 ring carbons and isadvantageously cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl optionally substituted by lower alkyl.

N-heterocyclyl is as defined above. Preferred N-heterocyclicsubstituents are optionally substituted pyrrolidine, pyrrole, diazole,triazole, tetrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine,triazine, piperidine, piperazine, morpholine, phthalimde, hydantoin,oxazolidinone or 2,6-dioxo-piperazine and, for example, as hereinafterdescribed in the examples.

In particular embodiments the invention provides a compound of formulaIb, Ic, II or IV or a pharmaceutically acceptable salt or ester thereof

wherein

-   R8′ is H or optionally substituted aryl-lower alkyl-   wherein R8′ is optionally substituted as defined above for R8, and    the other symbols are as defined above.

In a further preferred embodiment the invention provides a compound offormula VI or a pharmaceutically acceptable salt or ester thereof

wherein R2 and R15 are as defined above.

R2 is preferably lower alkyl, e.g. straight chain or more preferablybranched-chain C₁-C₆ alkyl, e.g. especially 2-ethylbutyl, isobutyl, or2,2-dimethylpropyl; or C₃-C₆cycloalkyl, especially cyclopropyl,cyclopentyl or cyclohexyl.

R15 is preferably 4-lower alkylpiperaz-1-yl-lower alkyl, 4-loweralkylpiperaz-1-yl-lower alkoxy-phenylamino, C₃-C₆cycloalkyl,C₃-C₆cycloalkylamino-lower alkyl, imidazo-lower alkyl, morpholino-loweralkyl, lower alkoxy-lower alkylamino-lower alkyl or aryl-loweralkylamino-lower alkyl. For example, R15 is cyclopentyl,4-methyl-piperaz-1-yl-ethyl, cyclohexylaminoethyl, imidazol-1-ylethyl,morpholinoethyl, methoxyethylaminoethyl,2-(3-(4-methyl-piperazin-1-yl)-propoxy)-phenylamino orphenylethylaminoethyl.

In a yet further preferred embodiment the invention provides a compoundof formula VII or a pharmaceutically acceptable salt or ester thereof

wherein R2 and R16 are as defined above.

Preferred significances for R2 in figure VII are as defined above forfigure VI.

R16 is preferably H, aryl-lower alkyl, aryl-lower-alkoxy,1-lower-alkyl-piperidin-2-yl-lower-alkoxy, 4-loweralkyl-piperazin-1-yl-lower alkyl, 4-lower alkyl-piperaz-1-yl-loweralkoxy, 4-loweralkoxy-lower alkyl-piperaz-1-yl-lower alkyl,4-loweralkoxy-lower alkyl-piperaz-1-yl-lower alkoxy,di-loweralkylamino-lower alkyl, di-loweralkylamino-lower alkoxy or loweralkyl-piperidyl-lower alkyl. For example, R16 is H,2-dimethlyamino-ethoxy, 2-(4-methyl-piperazin-1-yl)-ethoxy,3-(4-propyl-piperazin-1-yl)-propoxy,3-(4-(2-methoxy-ethyl)-piperazin-1-yl)-propoxy,3-(4-isopropyl-piperazin-1-yl)-propoxy, pyridin-4-ylmethoxy,pyridin-3-ylmethoxy, pyridin-2-ylmethoxy,1-methyl-piperidin-2-ylmethoxy, pyrid-3-ylmethyl, pyrid-4-ylmethyl,4-methyl-piperazin-1-ylethyl, 4-ethyl-piperazin-1-ylpropyl,4-isopropyl-piperazin-1-ylpropyl, 4-n-propyl-piperazin-1-ylethyl,4-(2-methoxyethyl)-piperazin-1-ylpropyl, dimethylaminopropyl or1-methyl-piperid-3-ylmethyl.

In a yet further preferred embodiment the invention provides a compoundof formula VIII or a pharmaceutically acceptable salt or ester thereof

wherein R9 and R5 are as defined above.

R9 is preferably R9′ which is lower alkyl, e.g. straight chain or morepreferably branched-chain C₁-C₆ alkyl, e.g. especially 2-ethylbutyl,isobutyl, or 2,2-dimethylpropyl; or C₃-C₆cycloalkyl, especiallycyclopropyl, cyclopentyl or cyclohexyl.

R5 is preferably optionally substituted (aryl-lower-alkyl,N-heterocyclyl-aryl, 1,2,3,4-tetrahydroisoquinlin-yl,aryl-N-heterocyclyl, lower-alkyl-carbonyl-aryl-N-heterocyclyl, aryloxy,N-heterocyclyl, N-heterocyclyl-lower-alkyl-aryloxy,N-heterocyclyl-arylcarbonyl, halo-lower-alkyl-sulphonyl-N-heterocyclyl,lower-alkoxy-aryl-sulphonyl-N-heterocyclyl,dilower-alkylaminoaryl-carbonyl-N-heterocyclyl,lower-alkylcarbonylamino-aryl-sulphonyl-N-heterocyclyl,halo-lower-alkylsulphonyl-N-heterocyclyl oraryl-lower-alkyl-N-heterocyclyl (where N-heterocyclyl is as definedabove)).

R5 is preferably optionally substituted by from 1-8 substituentsselected from halo, hydroxy, nitro, cyano, amino, oxo, lower-alkyl,lower-alkenyl, lower-alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower-alkyl, C₃-C₁₀cycloalkylamino, lower-alkoxy,lower-alkoxy-lower-alkyl, lower-alkoxy-lower-alkoxy-lower-alkyl,halo-lower-alkyl, lower-alkyl-carbonyl, aryl, aryl-lower-alkyl,halo-aryl-lower-alkyl, halo-aryloxy-lower-alkyl-carbonyl,lower-alkyl-sulphonyl, lower-alkyl-carbonyl, lower-alkoxy-carbonyl,sulphonamido, lower-alky-carbonyl-aryl, aryl,lower-alkyl-N-heterocyclyl-lower-alkyl, lower-alkylamino.Halo-lower-alkyl-sulphonyl, lower-alkoxy-aryl-sulphonyl,dilower-alkylamino-aryl-carbonyl, lower-alkyl-amido-aryl-sulphonyl orhalo-lower-alkyl-sulphonyl.

For example, R5 is benzyl, 4-(4-methyl-piperazin-1-yl)-phenyl,3,4-dihydro-1 H-isoquinolin-2-yl, 4-phenyl-piperazin-1-yl,4-(4-methylcarbonylphenyl)-piperazin-1-yl,4-phenyl-4-hydroxy-piperidin-1-yl, isoindol-2-yl, isoindol-1-yl,4-pyridin-2-yl-piperazin-1-yl, pyridin-3-yloxy, imidazol-1-yl,4,5-dichloro-imidazol-1-yl, 4-(4-methyl-piperazin-1-ylmethyl)-phenoxy,4-[1,2,3]triazol-1-yl-benzoyl,4-(3-chloro-propane-1-sulfonyl)-piperazin-1-yl,4-(4-methoxy-phenyl-sulfonyl)-piperazin-1-yl,4-(4-dimethylaminophenyl-carbonyl)-piperazin-1-yl,4-(4-methylcarbonylaminophenyl-sulfonyl)-piperazin-1-yl,4-(3-chloropropyl-sulfonyl)-piperazin-1-yl and4-benzyl-2,6-dioxo-piperazin-1-yl.

In a yet further preferred embodiment the invention provides a compoundof formula IX or a pharmaceutically acceptable salt or ester thereof

wherein R9 is as defined above and R8″ is optionally substitutedaryl-lower alkyl as defined above for R8′.

R9 is preferably R9′ which is lower alkyl, e.g. straight chain or morepreferably branched-chain C₁-C₆-alkyl, e.g. especially 2-ethylbutyl,isobutyl, or 2,2-dimethylpropyl; or C₃-C₆cycloalkyl, especiallycyclopropyl, cyclopentyl or cyclohexyl.

R8″ is preferably optionally substituted(N-heterocyclyl-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,loweralkylsulfonyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,C₃-C₁₀cyclcloalkylamino-loweralkynyl-aryl-loweralkyl,N-heterocyclylamino-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-loweralkynyl-aryl-loweralkyl,amino-loweralkyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,carboxy-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,hydroxy-loweralkyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-loweralkylamino-loweralkynyl-aryl-loweralkyl,amino-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-aminocarbonyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,di-loweralkyl-aminocarbonyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,hydroxy-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-aryl-loweralkyl, loweralkyl-aryl-loweralkyl,loweralkynyl-aryl-loweralkyl, N-heterocyclyl-loweralkyl-aryl-loweralkyl,loweralkyl-carbonyl-N-heterocyclyl-loweralkyl-aryl-loweralkyl,loweralkyl-sulfonyl-N-heterocyclyl-loweralkyl-aryl-loweralkyl,N-heterocyclyl-loweralkyl-aryl-loweralkyl,loweralkyl-sulfonyl-loweralkyl-aryl-loweralkyl,hydroxy-N-heterocyclyl-loweralkyl-aryl-loweralkyl,N-heterocyclylcarbonyloxy-loweralkyl-aryl-loweralkyl,N-heterocyclyl-loweralkynyl-aryl-loweralkyl,loweralkylsulphonyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl,N-heterocyclyl-N-heterocyclyl-loweralkynyl-aryl-loweralkyl orloweralkynyl-aryl-loweralkyl (where N-heterocyclyl is as definedabove)).

R8″ is preferably optionally substituted by from 1-8 substituentsselected from halo, hydroxy, nitro, cyano, amino, oxo, lower-alkyl,lower-alkenyl, lower-alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower-alkyl, C₃-C₁₀cyclcloalkylamino, lower-alkoxy,lower-alkoxy-lower-alkyl, lower-alkoxy-lower-alkoxy-lower-alkyl,halo-lower-alkyl,lower-alkyl-carbonyl, aryl, aryl-lower-alkyl,halo-aryl-lower-alkyl, halo-aryloxy-lower-alkyl-carbonyl,lower-alkyl-sulphonyl, lower-alkyl-carbonyl, lower-alkoxy-carbonyl,sulphonarnido, lower-alky-carbonyl-aryl, aryl,lower-alkyl-N-heterocyclyl-lower-alkyl, lower-alkylamino.Halo-lower-alkyl-sulphonyl, lower-alkoxy-aryl-sulphonyl,dilower-alkylamino-aryl-carbonyl, lower-alkyl-amido-aryl-sulphonyl orhalo-lower-alkyl-sulphonyl.

For example R8″ is 4-(3-(4-acetyl-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-formyl-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-piperidin-1-yl-prop-1-ynyl)-benzyl,4-(3-(4-methyl-piperzin-1-yl)-prop-1-ynyl)-benzyl,4-(3-pyrrol-1-yl-prop-1-ynyl)-benzyl,4-(3-(4-piperidin-1-yl-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-ethyl-piperazin-prop-1-ynyl)-benzyl,4-(3-(4-isopropyl-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-n-propylsulfonyl-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-hydroxy-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-oxo-piperazin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(cyclohexylamino)-prop-1-ynyl )-benzyl,4-(3-(piperidin-1-ylamino)-prop-1-ynyl)-benzyl,4-(3-(4-aminomethyl-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-hydroxycarbonyl-piperidin-1-yl)-prop-1-ynyl)-benzyl, 4-(3-(4-hydroxymethyl-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(morpholinoethylamino)-prop-1-ynyl)-benzyl,4-(3-(piperidinylethylamino)-prop-1-ynyl)-benzyl,4-(3-(imidazol-1-yl)-prop-1-ynyl)-benzyl,4-(3-([1,2,4]-triazol-prop-1-ynyl)-benzyl,4-(3-amino-prop-1-ynyl)-benzyl,4-(3-(4-[1,2,4]triazol-4-ylamino-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-( 3-(4-dimethylaminocarbonylpiperidin-1-yl)-prop-1-ynyl)-benzyl,4-(3-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-(3-(4-hydroxy-piperidin-1-yl)-prop-1-ynyl)-benzyl,4-[1,2,4]triazol-1-yl-benzyl, 4-imidazol-1-yl-benzyl, 4-vinyl-benzyl,4-(3-methyl-3H-imidazol-4-yl)-benzyl, 4-oxazol-2-yl-benzyl,4-[1,2,4]triazol-1-ylmethyl-benzyl, 4-imidazol-1-ylmethyl-benzyl,4-ethyl-benzyl, 3-(3-(4-acetyl-piperazin-1-yl)-propyl)-benzyl,3-(3-(4-ethylsulfonyl-piperazin-1-yl)-propyl)-benzyl,3-(3-(4-oxo-piperidin-1-yl)-propyl)-benzyl, 3-(3-(4-hydroxylamino-piperidin-1-yl)-propyl)-benzyl,4-(3-piperidin-1-yl-propyl)-benzyl,4-(2-methylsulfonyl-1-methyl-ethyl)-benzyl,4-(3-piperidin-1-yl-propyl)-benzyl, 4-(3-(4-hydroxy-piperidin-1-yl)-propyl)-benzyl,4-(3-(piperidin-4-yl-carbonyloxy)-propyl)-benzyl,4-((E)-3-piperidin-1-yl-propenyl)-benzyl,4-((E)-3-(2,6-dioxo-piperidin-1-yl)-propenyl)-benzyl,4-((l)-3-(4-hydroxy-piperidin-1-yl)-propenyl)-benzyl,4-((E)-3-(4-hydroxycarbonyl-piperidin-1-yl)-propenyl)-benzyl,4-((E)-3-pyrrolo-1-yl-propenyl)-benzyl, 4-((E)-3-(4-methylcarbonyl-piperazin-1-yl)-propenyl)-benzyl,4-((F)-3-(4-methyl-piperazin-1-yl)-propenyl)-benzyl,4-((E)-3-(4-ethyl-piperazin-1-yl)-propenyl)-benzyl,4-((E)-3-(4-ethylsulfonyl-piperazin-1-yl)-propenyl)-benzyl,4-((E)-3-(4-piperidin-1-yl-piperidin-1-yl)-propenyl)-benzyl,4-((E)-2-cyano-vinyl)-benzyl,4-((13)-2-([1,2,4]-triazol-1-yl)-vinyl)-benzyl,4-((E)-2-([1,2,3]-triazol-1-yl)-vinyl)-benzyl,4-(3-(4-hydroxyamino-piperidi-1-yl)-prop-1-ynyl)-benzyl and4-((E)-3-piperidin-1-yl-propenyl)-benzyl.

Particularly preferred compounds of the invention are the compounds ofthe examples

Compounds of formula VI or pharmaceutically acceptable salts or estersthereof

wherein R2 and R15 are as defined above, may be prepared by cyanation ofa corresponding 2-halo precursor of formula XIV

wherein R2 and R15 are as defined above and Halo is preferably Cl; forinstance substantially as described in the examples.

Compounds of formula VII or pharmaceutically acceptable salts or estersthereof

wherein R2 and R16 are as defined above, may be prepared by coupling ofa 6-hydroxy precursor of formula XV with an R16-Halo precursor

wherein R2 and R16 are as defined above and Halo preferably Cl; forinstance, substantially as described in the examples.

Compounds of formula VIII or pharmaceutically acceptable salts or estersthereof

wherein R2 and R5 are as defined above, may be prepared by coupling of a5-halopyrimidine precursor of formula XVI with a correspondingR5-CH₂—C=≡CH propyne

wherein R2 and R5 are as defined above and Halo is preferably Br; forinstance, substantially as described in the examples.

Compounds of formula IX or pharmaceutically acceptable salts or estersthereof

wherein R2 is as defined above and R8″ is optionally substitutedaryl-lower alkyl as defined above for R8′, may be prepared by couplingof a secondary amine precursor of formula XVII

wherein R2 is as defined above, with a corresponding R8″-Halo precursor,wherein Halo is preferably I; for instance, substantially as describedin the examples.

The above coupling, cyclisation and cyanation reactions may be carriedout under various conditions and in the presence of solvents and otherreagents as required, including catalysts and co-factors as known in theart and for instance, as hereinafter described in the examples.

The starting materials may be prepared and the coupled and cyclisedproducts may be converted into other compounds of formula V and saltsand esters thereof using methods and procedures known in the art, and ashereinafter described in the examples.

Accordingly the present invention further provides processes for thepreparation of compounds of Formula I

as hereinbefore defined, comprising i) for the preparation of compoundsof formula VI or pharmaceutically acceptable salts or esters thereof

wherein R2 and R15 are as defined above, cyanation of a corresponding2-halo precursor of formula XX

wherein R2 and R15 are as defined above and Halo is preferably Cl; ii)for preparation of compounds of formula VII or pharmaceuticallyacceptable salts or esters thereof

wherein R2 and R16 are as defined above, coupling of a 6-hydroxyprecursor of formula XV with an R16-Halo precursor

wherein R2 and R16 are as defined above and Halo is preferably Cl; iii)for the preparation of compounds of formula VIII or pharmaceuticallyacceptable salts or esters thereof

wherein R2 and R5 are as defined above, coupling of a 5-halopyrimidineprecursor of formula XVI with a corresponding R5-CH₂—C≡CH propyne

wherein R2 and R5 are as defined above and Halo is preferably Br; iv)for the preparation of compounds of formula IX or pharmaceuticallyacceptable salts or esters thereof

wherein R2 is as defined above and R8″ is optionally substitutedaryl-lower alkyl as defined above for R8′, coupling of a secondary amineprecursor of formula XVII

wherein R2 is as defined above, with a corresponding R8″-Halo precursor,wherein Halo is preferably I; v) thereafter, if desired, converting theproduct obtained into a further compound of formula I, or into a salt orester thereof

Compounds of the invention are either obtained in the free form, or as asalt thereof if salt forming groups are present.

Compounds of the Invention having basic groups can be converted intoacid addition salts, especially pharmaceutically acceptable salts. Theseare formed, for example, with inorganic acids, such as mineral acids,for example sulfuric acid, a phosphoric or hydrohalic acid, or withorganic carboxylic acids, such as (C₁-C₄)alkanecarboxylic acids which,for example, are unsubstituted or substituted by halogen, for exampleacetic acid, such as saturated or unsaturated dicarboxylic acids, forexample oxalic, succinic, maleic or fumaric acid, such ashydroxycarboxylic acids, for example glycolic, lactic, malic, tartaricor citric acid, such as amino acids, for example aspartic or glutamicacid, or with organic sulfonic acids, such as (C₁-C₄)-alkylsulfonicacids (for example methanesulfonic acid) or arylsulfonic acids which areunsubstituted or substituted (for example by halogen). Preferred aresalts formed with hydrochloric acid, methanesulfonic acid and maleicacid.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The compounds of the invention exhibit valuable pharmacologicalproperties in mammals and are particularly useful as inhibitors ofcathepsin K.

The cathepsin K inhibitory effects of the compound of the invention canbe demonstrated in vitro by measuring the inhibition of e.g. recombinanthuman cathepsin K. The in vitro assay is carried out as follows:

For cathepsin K:

The assay is performed in 96 well microtiter plates at ambienttemperature using recombinant human cathepsin K. Inhibition of cathepsinK is assayed at a constant enzyme (0.16 nM) and substrate concentration(54 mM Z-Phe-Arg-AMCA-Peptide Institute Inc. Osaka, Japan) in 100 mMsodium phosphate buffer, pH 7.0, containing 2 mM dithiothreitol, 20 mMTween 80 and 1 mM EDTA. Cathepsin K is preincubated with the inhibitorsfor 30 min, and the reaction is initiated by the addition of substrate.After 30 min incubation the reaction is stopped by the addition of E-64(2 mM), and fluorescence intensity is read on a multi-well plate readerat excitation and emission wavelengths of 360 and 460 nm, respectively.Compounds of the Invention typically have Kis for human cathepsin K ofless than about 50nM, preferably of about 5nM or less, e.g. about 1 nM.

In view of their activity as inhibitors of cathepsin K, Compounds of theInvention are particularly useful in mammals as agents for treatment andprophylaxis of diseases and medical conditions involving elevated levelsof cathepsin K. Such diseases include diseases involving infection byorganisms such as pneumocystis carinii, trypsanoma cruzi, trypsanomabrucei, crithidia fusiculata, as well as parasitic diseases such asschistosomiasis and malaria, tumours (tumour invasion and tumourmetastasis), and other diseases such as metachromatic leukodystrophy,muscular dystrophy, amytrophy and similar diseases.

Cathepsin K, has been implicated in diseases of excessive bone loss, andthus the Compounds of the Invention may be used for treatment andprophylaxis of such diseases, including osteoporosis, gingival diseasessuch as gingivitis and periodontitis, Paget's disease, hypercalcemia ofmalignancy, e.g. tumour-induced hypercalcemia and metabolic bonedisease. Also the Compounds of the Invention may be use for treatment orprophylaxis of diseases of excessive cartilage or matrix degradation,including osteoarthritis and rheumatoid arthritis as well as certainneoplastic diseases involving expression of high levels of proteolyticenzymes and matrix degradation.

Compounds of the Invention, are also indicated for preventing ortreating coronary disease, atherosclerosis (including atheroscleroticplaque rupture and destabilization), autoimmune diseases, respiratorydiseases and immunologically mediated diseases (including transplantrejection).

Compounds of the Invention are particularly indicated for preventing ortreating osteoporosis of various genesis (e.g. juvenile, menopausal,post-menopausal, post-traumatic, caused by old age or by cortico-steroidtherapy or inactivity).

Beneficial effects are evaluated in in vitro and in vivo pharmacologicaltests generally known in the art, and as illustrated herein.

The above cited properties are demonstrable in in vitro and in vivotests, using advantageously mammals, e.g. rats, mice, dogs, rabbits,monkeys or isolated organs and tissues, as well as mammalian enzymepreparations, either natural or prepared by e.g. recombinant technology.Compounds of the Invention can be applied in vitro in the form ofsolutions, e.g. preferably aqueous solutions or suspensions, and in vivoeither enterally or parenterally, advantageously orally, e.g. as asuspension or in aqueous solution, or as a solid capsule or tabletformulation. The dosage in vitro may range between about 10⁻⁵ molar and10⁻⁹ molar concentrations. The dosage in vivo may range, depending onthe route of administration, between about 0.1 and 100 mg/kg.

The antiarthritic efficacy of the Compounds of the Invention for thetreatment of rheumatoid arthritis can be determined using models such asor similar to the rat model of adjuvant arthritis, as describedpreviously (R. E. Esser, et. al. J. Rheumatology, 1993, 20, 1176.)

The efficacy of the compounds of the invention for the treatment ofosteoarthritis can be determined using models such as or similar to therabbit partial lateral meniscectomy model, as described previously(Colombo et al. Artl. Rheum. 1993 26, 875-886). The efficacy of thecompounds in the model can be quantified using histological scoringmethods, as described previously (O'Byrne et al. Inflamm Res 1995, 44,S117-S118).

The efficacy of the compounds of the invention for the treatment ofosteoporosis can be determined using an animal model such as theovariectomised rat or other similar species, e.g. rabbit or monkey, inwhich test compounds are administered to the animal and the presence ofmarkers of bone resorption are measured in urine or serum (e.g. asdescribed in Osteoporos Int (1997) 7:539-543).

Accordingly in further aspects the invention provides: A Compound of theInvention for use as a pharmaceutical; a pharmaceutical compositioncomprising a Compound of the Invention as an active ingredient; a methodof treating a patient suffering from or susceptible to a disease ormedical condition in which cathepsin K is implicated, comprisingadministering an effective amount of a Compound of the Invention to thepatient, and the use of a Compound of the Invention for the preparationof a medicament for therapeutic or prophylactic treatment of a diseaseor medical condition in which cathepsin K is implicated.

The present invention relates to methods of using Compounds of theInvention and their pharmaceutically acceptable salts, or pharmaceuticalcompositions thereof, in mammals for inhibiting cathepsin K, and for thetreatment of cathepsin K dependent conditions, such as the cathepsin Kdependent conditions, described herein, e.g. inflammation, osteoporosis,rheumatoid arthritis and osteoarthritis.

Particularly the present invention relates to a method of selectivelyinhibiting cathepsin K activity in a mammal which comprisesadministering to a mammal in need thereof an effective cathepsin Kinhibiting amount of a Compound of the Invention. More specifically suchrelates to a method of treating osteoporosis, rheumatoid arthritis,osteoarthritis, and inflammation (and other diseases as identifiedabove) in mammals comprises administering to a mammal in need thereof acorrespondingly effective amount of a Compound of the Invention. Thefollowing examples are intended to illustrate the invention and are notto be construed as being limitations thereon. Temperatures are given indegrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR).Abbreviations used are those conventional in the art.

EXAMPLES

Example 10 describes the preparation of purine-2-carbonitriles

Example 10-1 Synthesis of6-Cyclohexylamino-9-cyclopentyl-purine-2-carbonitrile A.(2-Chloro-purin-6-yl)-cyclohexyl-amine:

To a solution of 2,6-Dichloro-purine (10 mmol) in 1-pentanol (20 ml)cyclohexylamin (30 mmol) is added and the stirred mixture is heated at70° C. for 4 hours. The heating bath is removed and after cooling downto RT the precipitate formed is filtered off and washed with ethanol,diethylether and dried (vacuum). A solid powder with mp. 265° C.(decomp.), Rf=0.34 (CH₂Cl₂/MeOH=9:1) is obtained.

B. (2-Chloro-9-cyclopentyl-purin-6-yl)-cyclohexyl-amine:

2-Chloro-6-cyclohexylamino-purine (10 mmol), bromocyclopentane (20 mmol)and potassium carbonate (20 mmol, water free) in DMF (70 ml) are heatedup to 50° C. and the mixture is stirred at this temperature for 10hours. After cooling to RT the mixture is poured on water and extracted3 times with ethyl acetate. The combined organic phases are washed twicewith brine and the extract is dried over sodium sulfate and evaporated.A pale oil with Rf=0.36 (CH₂Cl₂/MeOH=20:1) is obtained.

C. 6-Cyclohexylamino-9-cyclopentyl-purine-2-carbonitrile:

2-Chloro-6-cyclohexylamino-9-cyclopentyl-purine (6.3 mmol) and sodiumcyanide (36 mmol) are heated up in DMF (30 ml) to 160° C. for 70 hours.After cooling down to RT the mixture is poured on water and extracted 3times with ethyl acetate. The combined organic phases are washed withbrine and the extract is dried over sodium sulfate and evaporated. Theresidue is purified by flash chromatography on silica gel with ethylacetate as mobile phase. The product containing fractions are combinedand evaporated. A pale yellow oil with Rf=0.33 (ethyl acetate) isobtained.

¹H-NMR (CDCl₃): 1.2-1.55 (m, 5H), 1.6-2.1 (m, 11H), 2.2-2.4 (m, 2H),4.05-4.2 (m, 1H), 4.854.95 (m, 1H), 5.7-5.9 (broad signal, 1H), 7.9 (s,1H).

Example 10-26-Cyclohexylamino-9-(2-imidazol-1-yl-ethyl)-purine-2-carbonitrile A:[2-Chloro-9-(2-chloro-ethyl)-purin-6-yl]-cyclohexyl-amine:

2-Chloro-6-cyclohexylamino-purine (4 mmol), 1-bromo-2-chloroethane (8mmol) and potassium carbonate (8 mmol, water free) in DMF (20 ml) areheated up to 45° C. and the mixture is stirred at this temperature for 5hours. After cooling to RT the mixture is poured on water and extracted3 times with ethyl acetate. The combined organic phases are washed twicewith brine and the extract is dried over sodium sulfate and evaporated.The residue is dissolved in diethylether and pentane is added. The solidmaterial formed is filtered of and dried (vacuum). A white powder withmp. 150-152° C., Rf=0.17 (CH₂Cl₂/MeOH=20:1) is obtained.

B: [2-Chloro-9-(2-imidazol-1-yl-ethyl)-9-purin-6-yl]-cyclohexyl-amine

[2-Chloro-9-(2-chloro-ethyl)-purin-6-yl]-cyclohexyl-amine (1 mmol) andsodium imidazol (1.3 mmol) are dissolved in DMF (10 ml) and heated up to80° C. and the mixture is stirred at this temperature for 7 hours. Afterevaporation of the solvent, the residue is dissolved in water andextracted three times with ethyl acetate. The combined extract is driedover sodium sulfate and evaporated. The residue is purified by flashchromatography on silica gel with (CH₂Cl₂/MeOH=10:1) as mobile phase.The product containing fractions are combined and evaporated. A pale oilwith Rf=0.40 (CH₂Cl₂/MeOH=10:1) is obtained.

C: 6-Cyclohexylamino-9-(2-imidazol-1-yl-ethyl)-purine-2-carbonitrile

[2-Chloro-9-(2-imidazol-1-yl-ethyl)-9-purin-6-yl]-cyclohexyl-amine (0.6mmol) and sodium cyanide (2 mmol) are heated up in DMA (3 ml) to 160° C.and the mixture is stirred at this temperature for 20 hours. Aftercooling down to RT the mixture is poured on water and extracted 3 timeswith ethyl acetate. The combined organic phases are washed with brineand the extract is dried over sodium sulfate and evaporated. The residueis suspended in CH₂Cl₂ and the solid material filtered off. The filtrateis concentrated and the obtained residue purified by flashchromatography on silica gel with (CH₂Cl₂/MeOH=20:1) as mobile phase.The product containing fractions are combined and evaporated. A solidpowder with mp. 115-117° C., Rf=0.59 (CH₂Cl₂/MeOH=10:1) is obtained.

¹H-NMR (CDCl₃): 0.8-0.9 (m, 1H), 1.2-1.85 (m, 1H), 2.0-2.2 (m, 2H),4.05-4.2 (br. m, 1H), 5.2 (d, 1H), 5.7-5.8 (br. m, 1H), 5.9 (d, 1H), 7.2(m, 1H), 8.05 (s, 1H).

The compounds of formula 10-1 as identified below in Table 10-1 areprepared analogously to the above examples immediately above, startingfrom the corresponding 2,4-dichloropurines. TABLE 10-1 10-1

R1 (* indicates the bond to the Melting point or molecular Exple No.nitrogen) R2 (* indicates the bond to the nitrogen) RF-value (mobilephase) weight by MS 10-3

0.32 (CH₂Cl₂/MeOH = 9:2) 166-168° C. 10-4

0.29 (CH₂Cl₂/MeOH = 10:1) 153-155° C. 10-5

0.29 (CH₂Cl₂/MeOH = 10:1) 150° C. 10-6

0.16 (CH₂Cl₂/MeOH = 10:1) M⁺ = 343.3 10-7

0.34 (CH₂Cl₂/MeOH = 20:1) M⁺ = 330.3 10-8

0.25 (CH₂Cl₂/MeOH = 10:1) 75-76° C. 10-9

0.16 (CH₂Cl₂/MeOH = 10:1) 108-110° C. 10-10

0.22 (CH₂Cl₂/MeOH = 10:1) 132-133° C.

Example 10-11 Synthesis of9-Cyclopentyl-6-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-purine-2-carbonitrileA: 1-(3-Chloro-propoxy)-2-nitro-benzene

2-Nitrophenol (70mmol ), 1-bromo-3-chloropropane (360 mmol), potassiumcarbonate (water free, 110 mmol), potassium iodide (2 mmol) andtetrabutyl-ammonium bromide (1 mmol) are suspended in acetone (130 ml)and heated up to 50° C. and the mixture is then stirred at thistemperature for 30 hours. After cooling down to RT the solid material isfiltered off and the filtrate is evaporated. The excess of1-bromo-3-chloropropane is distilled of under vacuum (70° C.). Ayellow-orange oil with R=0.55 (hexane/ethyl acetate=2:1) is obtained,which is used in the next step without further purification.

B: 2-(3-Chloro-propoxy)-phenylamine

1-(3-Chloro-propoxy)-2-nitro-benzene (˜60mmol) is dissolved in ethanol(200 ml) and platinum dioxide (0.5 g) is added. The stirred mixture istreated with hydrogen under normal pressure until the hydrogen uptakestopped. The catalyst is filtered off and the filtrate is evaporated. Apale yellow oil with Rf=0.3 (CH₂Cl₂) is obtained, which is used in thenext step without further purification.

C: [2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine

2,6-Dichioropurine (10 mmol) and 2-(3-Chloro-propoxy)-phenylamine (˜20mmol) are dissolved in 1-pentanol and heated up to 70° C. and themixture is stirred at this temperature for 5 hours. While cooling downto R the product precipitated. The solid material was filtered off andwashed with 1-pentanol and diethyl ether. A solid powder with mp. 205°C., Rf=0.42 (CH₂Cl₂/MeOH=10:1) is obtained.

D:[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine

[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine (3 mmol),bromo-cyclopentane (4.1 mmol) and potassium carbonate (water free, 3.6mmol) are suspended in DMF (20 ml) and heated up to 50° C. and themixture is stirred at this temperature for 5 hours. After cooling to RTthe mixture is poured on water and extracted 3 times with ethyl acetate.The combined organic phases are washed twice with brine and the extractis dried over sodium sulfate and evaporated. The residue is purified byflash chromatography on silica gel with (CH₂Cl₂/MeOH=20:1) as mobilephase. The product containing fractions are combined and evaporated. Theproduct is cristallized from diethyl ether/pentane, filtered off anddried. A solid powder with mp. 110-112° C., Rf=0.78 (CH₂Cl₂/MeOH=20:1)is obtained.

E:(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine

[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine(0.4 mmol) are stirred at RT in N-methylpiperazine (0.3 ml) for 12hours. The mixture is diluted with water and extracted 3 times withethyl acetate. The combined organic phases are washed with brine and theextract is dried over sodium sulfate and evaporated. The residue ispurified by flash chromatography on silica gel with (CH₂Cl₂/MeOH=9:1) asmobile phase. The product containing fractions are combined andevaporated. A pale oil with R=0.25 (CH₂Cl₂/MeOH=9:2) is obtained.

F:9-Cyclopentyl-6-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-purine-2-carbonitrile

(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine(0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) aresuspended in DMA (2 ml) and heated up to 160° C. and the mixture isstirred at this temperature for 24 hours. The mixture is diluted withwater and extracted 3 times with ethyl acetate. The combined organicphases are washed with brine and the extract is dried over sodiumsulfate and evaporated. The residue is dissolved in diethylether,filtered over powdered charcoal and cooled to 4° C. The solid materialformed is filtered of and dried (vacuum). A white powder with mp.136-138° C. is obtained.

¹H-NMR (CDCl₃): 1.7-2.2 (m, 10H), 2.3 (s, 3H), 2.3-2.4 (m, 2H), 2.4-2.7(m, 8H), 4.1-4.2 (m, 2H), 4.9-5.0 (m, 1H), 6.9-7.0 (m, 1H), 7.0-7.1 (m,2H), 8.0 (s, 1H), 8.4 (broad, s, 1H), 8.7 (m, 1H).

Example 10-11 Synthesis of9-Cyclopentyl-6-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-purine-2-carbonitrileA: 1-(3-Chloro-propoxy)-2-nitro-benzene

2-Nitrophenol (70 mmol), 1-bromo-3-chloropropane (360 mmol), potassiumcarbonate (water free, 110 mmol), potassium iodide (2 mmol) andtetrabutyl-ammonium bromide (1 mmol) are suspended in acetone (130 ml)and heated up to 50° C. and the mixture is then stirred at thistemperature for 30 hours. After cooling down to RT the solid material isfiltered off and the filtrate is evaporated. The excess of1-bromo-3-chloropropane is distilled of under vacuum (70° C.). Ayellow-orange oil with Rf=0.55 (hexane/ethyl acetate=2:1) is obtained,which is used in the next step without further purification.

B: 2-(3-Chloro-propoxy)-phenylamine

1-(3-Chloro-propoxy)-2-nitro-benzene (˜60 mmol) is dissolved in ethanol(200 ml) and platinum dioxide (0.5 g) is added. The stirred mixture istreated with hydrogen under normal pressure until the hydrogen uptakestopped. The catalyst is filtered off and the filtrate is evaporated. Apale yellow oil with Rf=0.3 (CH₂Cl₂) is obtained, which is used in thenext step without further purification.

C: [2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6yl)-amine

2,6-Dichloropurine (10 mmol) and 2-(3-Chloro-propoxy)-phenylamine (˜20mmol) are dissolved in 1-pentanol and heated up to 70° C. and themixture is stirred at this temperature for 5 hours. While cooling downto R the product precipitated. The solid material was filtered off andwashed with 1-pentanol and diethyl ether. A solid powder with mp. 205°C., Rf=0.42 (CH₂Cl₂/MeOH=10:1) is obtained.

D:[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine

[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine (3 mmol),bromo-cyclopentane (4.1 mmol) and potassium carbonate (water free, 3.6mmol) are suspended in DMF (20 ml) and heated up to 50° C. and themixture is stirred at this temperature for 5 hours. After cooling to RTthe mixture is poured on water and extracted 3 times with ethyl acetate.The combined organic phases are washed twice with brine and the extractis dried over sodium sulfate and evaporated. The residue is purified byflash chromatography on silica gel with (CH₂Cl₂/MeOH=20:1) as mobilephase. The product containing fractions are combined and evaporated. Theproduct is cristallized from diethyl ether/pentane, filtered off anddried. A solid powder with mp. 110-112° C., Rf=0.78 (CH₂Cl₂/MeOH=20:1)is obtained.

E:(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine

[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine(0.4 mmol) are stirred at RT in N-methylpiperazine (0.3 ml) for 12hours. The mixture is diluted with water and extracted 3 times withethyl acetate. The combined organic phases are washed with brine and theextract is dried over sodium sulfate and evaporated. The residue ispurified by flash chromatography on silica gel with (CH₂Cl₂/MeOH=9:1) asmobile phase. The product containing fractions are combined andevaporated. A pale oil with Rf=0.25 (CH₂Cl₂/MeOH=9:2) is obtained.

F:9-Cyclopentyl-6-{2-[3-(4-methyl-piperazin-1-yl)-propoxyl-phenylamino}-purine-2-carbonitrile

(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine(0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) aresuspended in DMA (2 ml) and heated up to 160° C. and the mixture isstirred at this temperature for 24 hours. The mixture is diluted withwater and extracted 3 times with ethyl acetate. The combined organicphases are washed with brine and the extract is dried over sodiumsulfate and evaporated. The residue is dissolved in diethylether,filtered over powdered charcoal and cooled to 4° C. The solid materialformed is filtered of and dried (vacuum). A white powder with mp.136-138° C. is obtained.

¹H-NMR (CDCl₃): 1.7-2.2 (m, 10H), 2.3 (s, 3H), 2.3-2.4 (m, 2H), 2.4-2.7(m, 8H), 4.1-4.2 (m, 2H), 4.9-5.0 (m, 1H), 6.9-7.0 (m, 1H), 7.0-7.1 (m,2H), 8.0 (s, 1H), 8.4 (broad s, 1H), 8.7 (m, 1H).

Example 11 describes the preparation of Quinazoline-carbonitriles

Example 11-1 Synthesis of4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile A:Ethoxy-imino-acetic acid ethyl ester

Nitriloacetic acid ethyl ester (83 mmol) was dissolved in diethyl ether(water free, 25 ml) and ethanol (water free, 85 mmol) was added and thestirred mixture cooled to 40 ° C. At this temperature, HCl (gaz, driedthrough concentrated sulfuric acid; 18 g total consumption) was bubbledinto the solution over 1 hour. The cooling bath was removed and at 0° C.the reaction mixture warmed up quickly (additional cooling required) andthe product precipitated. The solid material was filtered off, washedwith diethyl ether and dried.

B: 4,6-Dihydroxy-quinazoline-2-carboxylic acid ethyl ester

2-amino-5-hydroxy-benzoic acid (15 mmol) are suspended in ethanol (waterfree, 600 ml) and heated up to 60° C. and stirred. Then triethylamine(30 mmol) is added and a clear solution is formed. Ethoxy-imino-aceticacid ethyl ester (1 6.5 mmol) is added at 60° C. and after 15 minutesanother portion of triethylamine (15 mmol) is added and the mixturestirred for another 30 minutes. The mixture is cooled down to RT andleft at RT without stirring over night. The solid material formed wasfiltered off, washed with ethanol/ether and dried (vacuum). A pale brownpowder with mp. 258-260° C. (decomposition) is obtained.

C: 4,6-Dihydroxy-quinazoline-2-carboxylic acid amide

4,6-Dihydroxy-quinazoline-2-carboxylic acid ethyl ester (11 mmol) isdissolved in methanol (50 ml) containing ammonia (4N). The mixture isstirred for 3 hours and the solid material formed is filtered off. Apale powder with mp. 305° C. (decomposition) is obtained.

D: Acetic acid 2-carbamoyl-4-hydroxy-quinazolin-6-yl ester

4,6-Dihydroxy-quinazoline-2-carboxylic acid amide (12 mmol) aredissolved in warm DMF (20 ml) and triethylamine (13.2 mmol) is added tothe stirred mixture. After cooling to RT a solution of acetic acidanhydride in DMF (10 ml) is added dropwise and the mixture is stirredovernight. The solvent is removed and the solid material formed issuspended in ethanol and the solid filtered of and dried (vacuum). Apowder with mp. 250° C. is obtained.

E: Acetic acid 4-chloro-2-cyano-quinazolin-6-yl ester

To a mixture of acetic acid 2-carbamoyl-4-hydroxy-quinazolin-6-yl ester8.1 mmol) and N,N-dimethylanilin (9 mmol) POCl₃ (72 mmol) is added andthe stirred mixture is heated for 45 minutes at 100° C. The excess ofPOCl₃ is evaporated and the residue is treated with ice/water andextracted fast with ethyl acetate. The organic phase is washed withdiluted aqueous HCL-solution (0.1 N), dried over sodium sulfate andevaporated. The residue was dissolved in ethanol and the solid materialformed was filtered off and dried (vacuum). A powder with mp. 145-147°C., Rf=0.26 (CH₂Cl₂) is obtained.

F: 4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile

To the stirred suspension of acetic acid4-chloro-2-cyano-quinazolin-6-yl ester (4.4 mmol) in ethanol (40 ml)cyclopentylamine (3 ml) is added dropwise at RT. After stirring for 30minutes a clear solution is formed and the mixture is stirred for 2hours. Then, water (10 ml) is added and the mixture is left over nightwithout stirring. The solvent is removed and the water phase is madebasic with 2N NaOH (20 ml). The mixture is extracted with ethyl acetate.The water phase is then acidified with 4N aqueous HCl and extracted withethyl acetate. The organic phase is dried over sodium sulfate andevaporated. The residue is suspended in CH₂Cl₂ and the solid material isfiltered off and dried (vacuum). A pale brown, amorphous powder withRf=0.16 (CH₂C₂/MeOH=15:1) is obtained.

¹H-NMR (DMSO): 1.5-1.8 (m, 6H), 1.9-2.1 (m, 2H), 4.5 (m, 1H), 7.4 (dd,1H), 7.6-7.7 (m, 2H), 8.2 (d, 1H), 10.2-10.4 (broad s, 1H).

Example 11-2 Synthesis of4-Cyclopentylamino-6-(2-dimethylamino-ethoxy)-quinazoline-2-carbonitrile

4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol),(2-Chloro-ethyl)-dimethyl-amine hydrochloride (0.55 mmol) andcesiumcarbonate (3.5 mmol) are stirred in DMF (3 ml) at RT for 20 hours.The suspension is filtered, washed with little DMF and water is added tothe filtrate until the solution gets turbide. The precipitate formed isfiltered off and dried (vacuum). A white powder with mp. 158-160° C.,Rf=0.51 (CH₂C₂/MeOH=9:2) is obtained.

¹H-NMR (DMSO): 1.5-1.8 (m, 6H), 1.9-2.1 (m, 2H), 2.2 (s, 6H), 2.65 (m,2H), 4.15 (m, 2H), 4.55 (m, 1H), 7.5 (dd, 1H), 7.7 (d, 1H), 7.8 (m, 1H),8.3 (broad d, 1H).

Example 11-3 Synthesis of4-Cyclopentylamino-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazoline-2-carbonitrile

4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol),1-(2-Chloro-ethyl)-4-methyl-piperazine dihydrochloride (0.55 mmol) andcesium carbonate (4 mmol) are stirred in DMF (5 ml) at RT for 20 hours.The suspension is filtered, washed with little DMF and water is added tothe filtrate until the solution gets turbide. The precipitate formed isfiltered off, washed with water and dried (vacuum). A powder with mp.110-112° C., Rf=0.48 (CH₂Cl₂/MeOH=9:2) is obtained.

¹H-NMR (CDCl₃): 1.5-1.9 (m, 6H), 2.2 (m, 2H), 2.35 (s, 31), 2.4-2.75 (m,8H), 2.9 (m, 2H), 4.25 (m, 2H), 4.6 (m, 1H), 6.85 (broad d, 1H), 7.05(d, 1H), 7.45 (dd, 1H), 7.8 (d, 1H).

Example 11-44-(2,2-Dimethyl-propylamino)-6-[3-(4-propyl-piperazin-1-yl)-propoxy]-quinazoline-2-carbonitrileA: 4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile

To the stirred suspension of acetic acid4-chloro-2-cyano-quinazolin-6-yl ester (4 mmol) in ethanol (30 ml)2,2-dimethyl-propylamine (1.4 ml) is added dropwise at RT. The mixtureis stirred for 3 hours. Then, water (3 ml) is added and the solvent isevaporated. The residue is dissolved in water and 1N NaOH to ensurebasic conditions. The mixture is extracted once with ethyl acetate. Thewater phase is then acidified with 4N aqueous HCl and extracted withethyl acetate. The organic phase is dried over sodium sulfate andevaporated. The residue is dissolved in hot ethanol an the solidmaterial formed after cooling is filtered off and dried (vacuum).Apowder with Rf=0.13 (CH₂Cl₂/MeOH=15:1) is obtained.

B:4-(2,2-Dimethyl-propylamino)-6-[3-(4-propyl-piperazin-1-yl)-propoxy]-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31mmol), 1-(3-chloro-propyl)4-propyl-piperazine (0.62 mmol) and cesiumcarbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 102-104° C.,Rf=4 (CH₂Cl₂/MeOH=9:2) is obtained.

¹H-NMR (CDCl₃): 0.9 (t, 3H), 1.05 (s, 9H), 1.4-1.6 (m, 2H), 2.0-2.1 (m,2H), 2.3 (m, 2H), 2.4-2.6 (m, 8H), 3.55 (m, 2H), 4.15 (m, 2H), 5.85(broad m, 1H), 6.95 (m, 1H), 7.45 (dd, 1H), 7.8 (d, 1H).

Example 11-54-(2,2-Dimethyl-propylamino)-6-{3-[4-(2-methoxy-ethyl)-piperazin-1-yl]-propoxy}-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesiumcarbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 92-94° C.,Rf=0.45 (CH₂Cl₂/MeOH=9:2) is obtained.

¹H-NMR (CDCl₃): 1.05 (s, 9H), 2.0-2.1 (m, 2H), 2.3 (m, 2H), 2.4-2.6 (m,12H), 3.35 (s, 3H), 3.45-3.6 (m, 4H), 4.15 (m, 2H), 5.75 (broad m, 1H),6.95 (m, 1H), 7.45 (dd, 1H), 7.8 (d, 1H).

Example 11-64-(2,2-Dimethyl-propylamino)-6-[3-(4-isopropyl-piperazin-1-yl)-propoxy]-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesiumcarbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 103-105° C.,Rf=0.4 (CH₂Cl₂/MeOH=9:2) is obtained.

¹H-NMR (CDCl₃): 1.0-1.1 (m, 15H), 2.0-2.1 (m, 2H), 2.4-2.7 (m, 11H),3.55 (m, 2H), 4.15 (m, 2H), 5.85 (broad m, 1H), 6.95 (m, 1H), 7.45 (dd,1H), 7.8. (d, 11).

Example 11-74-(2,2-Dimethyl-propylamino)-6-(pyridin-4-ylmethoxy)-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23mmol), 4-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesiumcarbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 203-205° C.,Rf=0.2 (CH₂Cl₂/MeOH=15:1) is obtained. ¹H-NMR (CDCl₃): 1.0 (m, 9H), 3.55(m, 2H), 5.2 (m, 2H), 5.8 (broad m, 1H), 7.05 (m, 1H), 7.4 (m, 2H), 7.55(d, 1H), 7.85 (d, 1H), 8.65 (m, 2H).

Example 11-84-(2,2-Dimethyl-propylamino)-6-(pyridin-3-ylmethoxy)-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.25mmol), 3-chloromethyl-pyridine hydrochloride (0.38 mmol) and cesiumcarbonate (2.5 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 156-158° C.,Rf=0.35 (CH₂Cl₂/MeOH=15:1) is obtained.

¹H-NMR (CDCl₃): 1.0 (m, 9H), 3.55 (m, 2H), 5.2 (m, 2H), 5.8 (broad m,1H), 7.05 (m, 1H), 7.35 (m, 1H), 7.55 (m, 1H), 7.8-7.9 (m, 2H). 8.65 (m,1H), 8.75 (m, 1H).

Example 11-94-(2,2-Dimethyl-propylamino)-6-(pyridin-2-ylmethoxy)-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23mmol), 2-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesiumcarbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Wateris added until a clear solution is formed. Then more water is addeduntil the solution gets turbide. The precipitate formed is filtered off,washed with water and dried (vacuum). A powder with mp. 160° C., R=0.4(CH₂Cl₂/MeOH=15:1) is obtained.

¹H-NMR (CDCl₃): 1.0 (m, 9H), 3.55 (m, 2H), 5.35 (m, 2H), 6.05 (broad m,1H), 7.2-7.3 (m, 2H), 7.45-7.6 (m, 2H), 7.7-7.85 (m, 2H), 8.6 (m, 1H).

Example 11-104-(2,2-Dimethyl-propylamino)-6-(1-methyl-piperidin-2-ylmethoxy)-quinazoline-2-carbonitrile

4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.3 1mmol), 1-methyl-2-chloromethyl-piperidine hydrochloride (0.41 mmol) andpotassium carbonate (7.2 mmol) are stirred in DMF (3 ml) at 80° C. for 8hours. The solvent is evaporated, the residue is dissolved in water andextracted with ethyl acetate. The organic phase is dried over sodiumsulfate and evaporated. The residue is purified by flash chromatographyon silica gel with (CH₂Cl₂/MeOH=9:1) as mobile phase. The productcontaining fractions are combined and evaporated. A pale oil withRf=0.54 (CH₂Cl₂/MeOH=10:1) is obtained.

¹H-NMR (CDCl₃): 1.05 (m, 9H), 1.3-1.45 (m, 1H), 1.6-1.9 (m, 5H), 2.2(m,1H), 2.35 (m, 1H), 2.4 (s, 3H), 2.9-3.0 (m, 1H) 3.55 (m, 2H),4.1-4.25 (m, 2H), 5.8 (broad m, 1H), 7.05 (m, 1H), 7.5 (dd, 1H), 7.85(d, 1H).

The following compounds of formula 11-1, as identified in Table 11-1below are prepared Analogously to the above examples, starting from thecorresponding substituted 4-amino-6-hydroxy-quinazoline-2-carbonitrile.TABLE 11-1 11-1

Melting point or molecular Ex. No R1 (* indicates the bond to thenitrogen) R2 (* indicates the bond to the oxygen) RF-value (mobilephase) weight by MS. 11-11

0.1 (CH₂Cl₂/MeOH = 15:1) 144-146° C. 11-12

0.29 (CH₂Cl₂/MeOH = 15:1) 212-214° C. 11-13

0.5 (CH₂Cl₂/MeOH = 9:2) M⁺ = 439.3 11-14

0.42 (CH₂Cl₂/MeOH = 9:2) 155° C. 11-15

0.6 (CH₂Cl₂/MeOH = 9:2) 145-148° C. 11-16

0.4 (CH₂Cl₂/MeOH = 9:2) 118-120° C. 11-17

0.18 (CH₂Cl₂/MeOH = 9:2) M⁺ = 368.3 11-18

0.3 (CH₂Cl₂/MeOH = 9:2) 105-107° C. 11-19

0.45 (CH₂Cl₂/MeOH = 9:2) 65-67° C. 11-20

0.25 (CH₂Cl₂/MeOH = 9:2) 70-72° C. 11-21

0.65 (CH₂Cl₂/MeOH = 9:2) 95° C. 11-22

0.74 (CH₂Cl₂/MeOH = 9:2) 100° C. 11-23

0.35 (CH₂Cl₂/MeOH = 9:2) 95-97° C. 11-24

0.4 (CH₂Cl₂/MeOH = 9:2) 133-135° C.

Example 12 describes the preparation of 5-substituted-pyrimidine-2-carbonitriles

Example 12-14-Cyclopentylamino-5-(4-phenyl-but-1-ynyl)-pyrimidine-2-carbonitrile

5-Bromo-4-cyclopentylamino-pyrimidine-2-carbonitrile (0.69 mmol),4-phenyl-1-butyne (1.66 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.035 mmol), copper (I)iodide (0.07 mmol) and triethylamine (2.1 mmol) in DMF (5 ml) is stirredat 75° C. for 2.5 h. The reaction mixture is treated with saturatedammonium chloride and extracted with AcOEt. The organic layer is washedwith brine, dried over magnesium sulfate and evaporated down. The crudeproduct is applied to a silica gel column chromatography, which iseluted with following solvents: n-hexane:AcOEt=12:1 (v/v) andn-hexane:AcOEt=10:1 (v/v). The solvent of the latter effluent is removedby evaporation and dried in vacuo to afford the title compound. yield89.9%, Rf=0.65 (n-hexane:AcOEt=2:1).

¹H-NMR (400 MHz, CDCl₃) 8 1.26-1.33(m, 2H), 1.64-1.71(m, 4H),2.05-2.09(m, 3H), 2.79-2.86(m, 2H), 2.94-3.00(m, 2H), 4.30-4.38(m, 2H),5.36-534(m, 1H), 7.35-7.21(m, 5H), 8.10(s, 1H),

12-24-(2,2-Dimethyl-propylamino)-5-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-prop-1-ynyl}-pyrimidine-2-carbonitrile

A. 1-[4-(4-Methyl-piperazin-1-yl)-phenyl]-prop-2-yn-1-ol

To a solution of 4-(4-methyl-piperazin-1-yl)-benzaldehyde (28.9 mmol) inTHF (100 ml), ethnylmagnesium bromide (0.5M solution in THF) (43.4 mmol)is added at −78° C. The solution is then stirred at room temperature for18 h. The reaction mixture is treated with saturated ammonium chlorideand extracted with ethyl acetate. The organic layer is washed withbrine, dried over magnesium sulfate and evaporated down. CH₂Cl₂ is addedto the residue to afford a precipitate, which is collected byfiltration. yield 84.2%, Rf=0.23 (CH₂Cl₂:MeOH=9:1).

B. 1-Methyl4-(4-prop-2-ynyl-phenyl)-piperazine

To a stirred mixture of glacial acetic acid (72 ml) and trifluoroaceticacid (8 ml), NaBH₄ (79.1 mmol) is added slowly under nitrogen at −15° C.The solution of 1-[4-(4-methyl-piperazin-1-yl)-phenyl]-prop-2-yn-1-ol (11.3 mmol) in CH₂Cl₂ (80 ml) is added dropwise over 0.5 h and the mixtureis stirred at room temperature for 1 h. The solvents are removed underreduced pressure and the residue is added to saturated sodiumbicarbonate. The aqueous solution is extracted with CH₂Cl₂. The organiclayer is washed with brine, dried over magnesium sulfate and evaporateddown. The crude product is applied to silica gel column chromatography,which is eluted with following solvents: CH₂Cl₂ and 5% MeOH in CH₂Cl₂.The solvent of the latter effluent is removed by evaporation and driedin vacuo to afford the title compound. yield 86.8%, Rf=0.52(CH₂Cl₂:MeOH=9:1).

C.4-(2,2-Dimethyl-propylamino)-5-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-prop-1-ynyl}-pyrimidine-2-carbonitrile

To a solution of 1-methyl-4-(4-prop-2-ynyl-phenyl)-piperazine (0.75mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile(0.5 mmol) in THF (7 ml), triethylamine (1.5 mmol),dichlorobis(triphenylphosphine)palladium (II) (0.025 mmol) and copper(I) iodide (0.05 mmol) are added. The reaction mixture is heated at 60°C. ca. for 3 h. Saturated aqueous solution of ammonium chloride is addedto the reaction mixture and then aqueous layer is extracted with two 50ml portions of AcOEt. The combined extracts are washed with brine, driedover sodium sulfate and concentrated under vacuum to give crude productwhich is purified by reverse phase HPLC. Yield: 25%. Rf=0.5(MeOH:CH₂Cl₂=5:95)

¹H NMR(400 MHz, CDCl₃) δ 0.91(s, 9H), 2.38(s, 3H), 2.61 (m, 4H), 3.21(t,4H), 3.32(d, 2H), 3.83(s, 2H), 5.75(s, 1H), 6.91(d, 2H), 7.24(d, 2H),8.19(s, 1H)

The preparation of starting materials.

2-Prop-2-ynyl-1,2,3,4-tetrahydro-isoquinoline

To 1,2,3,4-tetrahydro-isoquinoline (9.4 mmol) in DMF (10 ml),3-bromo-propyne (4.5 mmol) is added at 0° C. and stirred at roomtemperature for 18 h. After the reaction mixture is treated withsaturated ammonium chloride, the mixture is extracted with AcOEt. Theorganic layer is washed with brine, dried over magnesium sulfate andevaporated down. The crude product is applied to a silica gel columnchromatography, which is eluted with following solvents: n-hexane andn-hexane:AcOEt=1:1 (v/v). The solvent of the latter effluent is removedby evaporation and dried in vacuo to afford the title compound. yield91.2%, Rf=0.67 (n-hexane:AcOEt=1:5).

By repeating the procedures described immediately above usingappropriate starting materials and conditions the following compounds offormula 12-1 are obtained as identified below in Table 12-1. TABLE 12-112-1

Rx Yield (%) Rf (Solvent) ¹H-NMR(400 MHz, δ)

10.0 0.67 (CH₂Cl₂:MeOH = 9:1) (CDCl₃): 2.28(t, 1H), 2.73-2.76(m, 4H),3.23-3.26(m, 4H), 3.37(d, 2H), 6.86(t, 1H), 6.93(d, 2H), 7.24-7.31(m,2H),

91.2 0.67 (n-hexane:AcOEt = 1:5) (CDCl₃): 2.27(t, 1H), 2.83-2.86(m, 4H),2.91-2.95(m, 4H), 3.51(d, 2H), 3.77(s, 2H), 7.05-7.13(m, 4H),

73.7 0.37 (CH₂Cl₂:MeOH = 9:1) (CDCl₃): 2.28(t, 1H), 2.52(s, 3H),2.66-2.68(m, 4H), 3.37-3.44(m, 6H), 6.86(d, 2H), 7.86(d, 2H),

65.3 0.32 (n-hexane:AcOEt = 1:5) (CDCl₃): 1.78-1.82(m, 2H), 2.17-2.24(m,2H), 2.28(t, 1H), 2.67-2.73(m, 2H), 2.82-2.85(m, 2H), 3.36(d, 2H),2.25-2.29(m, 1H), 7.38(t, 2H), 7.50(d, 2H),

87.9 0.41 (n-hexane:AcOEt = 1:1) (CDCl₃): 2.29(t, 1H), 3.64(d, 2H),4.07(s, 4H), 7.21(s, 4H),

12-35-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)-prop-1-ynyl]-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile

2-Prop-2-ynyl-1,2,3,4-tetrahydro-isoquinoline (0.72 mmol),5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.86mmol), Bis(benzonitrile)-palladium(II)chloride (0.02 mmol), copper (I)iodide (0.015 mmol), tri-tert-butylphosphine (0.04 mmol) and diisopropylamine (0.86 mmol) in dioxane (4 ml) is stirred at room temperature for2.5 h. After filtration, the reaction mixture is treated with saturatedammonium chloride. The mixture is extracted with AcOEt. The organiclayer is washed with brine, dried over magnesium sulfate and evaporateddown. The crude product is applied to a column of silica gel, which iseluted with following solvents: n-hexane:AcOEt=1:1 (v/v) andn-hexane:AcOEt=1:5 (v/v). The solvent of the latter effluent is removedby evaporation and dried in vacuo to afford the title compound. yield46.5%, Rf=0.31 (n-hexane:AcOEt=1:1).

By repeating the procedures described above using appropriate startingmaterials and conditions the following compounds of formula 12-2 areobtained as identified below in Table 12-2.

TABLE 12-2 Expl. No. Rx Yield (%) Rf (Solvent) ¹H-NMR (400 MHz, δ) 12-4

41.0 0.43 (CH₂Cl₂:MeOH = 9:1) (CDCl₃): 0.97(s, 9H), 2.78-2.81(m, 4H),3.25-3.27(m, 4H), 3.37(d, 2H), 3.69(s, 2H), 5.84(br, 1H), 6.87-6.94(m,3H), 7.26-7.30(m, 2H), 8.22(s, 1H), 12-3

46.5 0.31 (n-hexane:AcOEt = 1:1) (CDCl₃): 0.95(s, 9H), 2.88-2.99(m, 4H),3.36(d, 2H), 3.76(s, 4H), 5.84(br, 1H), 7.00-7.04(m, 1H), 7.12-7.18(m,3H), 8.21(s, 1H), 12-5

63.0 0.21 (n-hexane:AcOEt = 1:5) (CDCl₃): 0.97(s, 9H), 2.53(s, 3H),2.76-2.79(m, 4H), 3.36-3.43(m, 6H), 3.70(s, 2H), 5.79(br, 1H), 6.87(d,2H), 7.88(d, 2H), 8.22(s, 1H), 12-6

26.1 0.28 (n-hexane:AcOEt = 1:5) (CDCl₃): 0.98(s, 9H), 1.46(s, 1H),1.81-1.85(m, 2H), 2.17-2.25(m, 2H), 2.75-2.89(m, 4H), 3.38(d, 2H),3.68(s, 2H), 5.89(br, 1H), 7.26-7.30(m, 1H), 7.38(t, 2H), 7.50(d, 2H),8.22(s, 1H), 12-7

65.1 0.32 (n-hexane:AcOEt = 1:5) (CDCl₃): 0.91(s, 9H), 3.33(d, 2H),3.95(s, 2H), 4.13(s, 4H), 5.78(br, 1H), 7.22(s, 4H), 8.13(s, 1H),

12-84-(2,2-Dimethyl-propylamino)-5-[3-(4-pyridin-2-yl-piperazin-1-yl)-prop-1-ynyl]-pyrimidine-2-carbonitrile

1-(2-Propynyl)-4-(2-pyridinyl)-piperazine (prepared from1-(2-pyridinyl)-piperazine and propargyl bromide) (1.5 mmol) isdissolved in DMF at room temperature under nitrogen atmosphere. To thesolution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile(1 mmol), triethylamine (3 mmol), copper(I) iodide (0.1 mmol), anddichlorobis(triphenylphosphine)palladium(II) (0.05 mmol) are addedsuccessively. The mixture is heated at 80° C. under nitrogen atmospherefor 3 h. After cooling at room temperature, the mixture is diluted withH₂O and extracted with AcOEt. The organic layer is dried over magnesiumsulfate and evaporated in vacuo. The residue is purified by silica gelcolumn chromatography (n-hexane:AcOEt=1:5) to give4-(2,2-dimethyl-propylamino)-5-[3-(4-pyridin-2-yl-piperazin-1-yl)-prop-1-ynyl]-pyrimidine-2-carbonitrile.Yield 97%. Rf=0.30 (n-hexane:AcOEt=1:5). ¹H NMR (400 MHz, CDCl₃) δ0.95(s, 9H), 2.75-2.73(m, 4H), 3.36(d, 2H), 3.63-3.60(m, 4H), 3.69(s,2H), 5.78(brs, 1H), 6.63-6.67(m, 2H), 7.47-7.52(m, 1H), 8.19-8.21(m,2H).

By repeating the procedure described above using appropriate startingmaterials and conditions, the following compounds of Formula 12-3 areobtained as identified below in Table 12-3. TABLE 12-3 12-3

Expl. No. Rx Yield (%) Rf (Solvent) ¹H NMR(400 MHz, δ) 12-9

17 0.45 (n-hexane:AcOEt = 1:1) 0.82(s, 9H), 3.30(d, 2H), 4.42(s, 2H),4.55(s, 2H), 6.50(brs, 1H), 7.44(d, 1H), 7.57(t, 1H), 7.64-7.68(m, 1H),7.81(d, 1H), 8.14(s, 1H) 12-10

10 0.47 (n-hexane:AcOEt = 1:1) (CDCl₃): 1.12(s, 9H), 4.17(s, 2H),5.64(s, 2H), 6.18(s, 1H), 7.23(d, 1H), 7.29-7.37(m, 2H), 7.89(d, 1H),7.95(s, 1H), 8.85(s, 1H) 12-11

72 0.26 (AcOEt) (CDCl₃): 0.89(s, 9H), 3.32(d, 2H), 5.06(s, 2H),5.64(brs, 1H), 7.27-7.34(m, 1H), 8.22(s, 1H), 8.31(brd, 1H), 8.42(brd,1H) 12-12

44 0.34 (CH₂Cl₂:MeOH = 95:5) (CDCl₃): 1.16-1.29(m, 2H), 1.38-1.50(m,2H), 1.64-1.79(m, 3H), 1.94-2.04(m, 2H), 3.96-4.08(m, 1H), 5.07(s, 2H),5.32-5.41(m, 1H), 7.09(bs, 1H), 7.17(bs, 1H), 7.64(bs, 1H), 8.23(s, 1H)12-13

57 0.49 (n-hexane:AcOEt = 1:1) (CDCl₃): 0.95(s, 9H), 3.37(d, 2H),5.01(s, 2H), 5.63(bs, 1H), 7.55(s, 1H), 8.24(s, 1H)

12-144-Cyclohexylamino-5-{3-[4-(4-methyl-piperazin-1-ylmethyl)-phenoxyl-prop-1-ynyl}-pyrimidine-2-carbonitrile

A.5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]-4-cyclohexylamino-pyrimidine-2-carbonitrile

5-Bromo-4-cyclohexylamino-pyrimidine-2-carbonitrile (0.19 mmol) andchloromethyl-4-prop-2-ynyloxy-benzene (0.22 mmol) in DMF (5 ml) aretreated with triethylamine (0.56 mmol), copper (I) iodide (0.019 mmol),and dichlorobis(triphenylphosphine)palladium(II) (0.0093 mmol) at roomtemperature. The mixture is stirred for 2 h at 65° C., poured into anice water, extracted with AcOEt. The organic layer is washed with brine,dried over magnesium sulfate and concentrated. The crude product ispurified by silica gel column chromatography to give the product in 21%yield. Rf=0.75 (n-hexanes:AcOEt=1:2). ¹H-NMR (400 MHz, CDCl₃) δ1.02-1.48 (m, 5H), 1.57-1.78 (m, 3H), 1.80-1.98 (m. 2H), 3.94-4.04 (m,1H), 4.61(s, 2H), 5.03 (s, 2H), 5.38 (d, 1H), 7.04 (d, 2H), 7.41 (d,2H), 8.21 (s, 1H).

B.4-Cyclohexylamino-5-{3-[4-(4-methyl-piperazin-1-ylmethyl)-phenoxy]-prop-1-ynyl}-pyrimidine-2-carbonitrile

5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]4-cyclohexylamino-pyrimidine-2-carbonitrile(0.050 mmol) is dissolved in CH₂Cl₂ (2 ml) and 1-methyl-piperazine (0.10mmol) is added at room temperature and the mixture is stirred at roomtemperature for overnight. Water is added and the organic layer iswashed with brine, dried over magnesium sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to givethe product in 40% yield.

By repeating the procedures described in the above example usingappropriate starting materials and conditions the following compounds offormula 12-4 are obtained as identified below in Table 12-4. TABLE 12-412-4

Expl. Nos. R1 R2 Yield (%) Rf (Solvent) ¹H-NMR (400 MHz, δ) 12-15

40 0.60 (CH₂Cl₂:MeOH = 5:1) (CDCl₃): 1.02-1.43(m, 5H), 1.61-1.75(m, 3H),1.86-1.98(m, 2H), 2.28(s, 3H), 2.54(brs, 8H), 3.46(s, 2H), 3.89-4.01(m,1H), 4.97(s, 2H), 5.38(d, 1H), 6.89(d, 2H), 7.28(d, 2H), 8.19(s, 1H).12-16

24 0.57 (CH₂Cl₂:MeOH = 5:1) (CDCl₃): 0.99-1.46(m, 6H), 1.75-1.95(m, 4H),2.38(s, 3H), 2.56-2.74(m, 6H), 3.59(s, 2H), 3.89-4.01(m, 1H), 4.97(s,2H), 5.38(d, 1H), 6.98(d, 2H), 7.30(d, 2H), 8.19(s, 1H). 12-17

82 0.58 (CH₂Cl₂:MeOH = 5:1) (CDCl₃): 0.89(s, 9H), 2.35(s, 3H), 2.47(brs,8H), 3.29(s, 2H), 3.51(s, 2H), 5.03(s, 2H), 5.68(brt, 1H), 7.00(d, 2H),7.32(d, 2H), 8.25(s, 1H).

12-184-(2,2-Dimethyl-propylamino)-5-[3-oxo-3-(4-[1,2,3]triazol-1-yl-phenyl)-prop-1-ynyl]-pyrimidine-2-carbonitrile

A. 4-(2,2-Dimethyl-propylamino)-5-ethynyl-pyrimidine-2-carbonitrile

5-Bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (7.58mmol) and ethynyl-trimethyl-silane (22.74 mmol) in DMF (20 ml) aretreated with triethylamine (38.0 mmol), copper (I) iodide (0.76 mmol),and dichlorobis(triphenylphosphine)palladium(II) (0.38 mmol) at roomtemperature. The mixture is stirred for 1.5 h at room temperature,poured into an ice water and extracted with AcOEt. The organic layer iswashed with brine, dried over magnesium sulfate and concentrated. Thecrude product is dissolved in methanol (60 ml)—water (10 ml) and cesiumfluoride (4.2 mmol) is added at room temperature and the mixture isstirred at room temperature for 5 min. The reaction mixture isevaporated, then water and CH₂Cl₂ are added. The organic layer is washedwith brine, dried over magnesium sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give theproduct in 76% yield. Rf=0.67 (n-hexane:AcOEt=2:1)

¹H-NMR (400 MHz, CDCl₃) δ 1.00 (s, 9H), 3.50 (d, 2H), 3.57 (s, 1H), 5.79(brt, 1H). 8.25 (s, 1H).

B.4-(2,2-Dimethyl-propylamino)-5-[3-oxo-3-(4-[1,2,3]triazol-1-yl-phenyl)-prop-1-ynyl]-pyrimidine-2-carbonitrile

4-[1,2,3]Triazol-1-yl-benzoic acid (5.0 mmol) is dissolved in CH₂Cl₂ (20ml). Oxalyl chloride (3.5 mmol) and DMF (1 drop) are added at roomtemperature and the reaction mixture is stirred at room temperature for3 h, then evaporated. The residue is dissolved in CH₂C₂ (20 ml) and themixture is added to4-(2,2-dimethyl-propylamino)-5-ethynyl-pyrimidine-2-carbonitrile, copper(I) iodide (0.13 mmol) and triethylamine (13.0 mmol) at roomtemperature. The reaction mixture is stirred for overnight at roomtemperature. The organic layer is washed with brine, dried overmagnesium sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give the product in 31% yield.Rf=0.02 (n-hexane:AcOEt=2:1)

¹H-NMR (400 MHz, CDCl₃) δ 1.03 (s, 9H), 3.40 (d, 2H), 6.09 (brt, 1H),7.92 (d, 1H), 8.01 (d, 2H), 8.16 (d, 1H), 8.33 (d, 2H), 8.49 (s, 1H).

12-195-{3-[4-(3-Chloro-propane-1-sulfonyl)-piperazin-1-yl]-prop-1-ynyl}-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile

A.4-{3-[2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-yl]-prop-2-ynyl}-piperazine-1-carboxylicacid .tert.-butyl ester

To a solution of 4-prop-2-ynyl-piperazine-1-carboxylic acid tert.-butylester (1.5 mmol) and5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (1 mmol)in DMF (6 ml), triethylamine (3.0 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.1 mmol) and copper (I)iodide (0.2 mmol) are added. The reaction mixture is heated at 85° C.ca. for 1 day. The mixture is quenched with ammonium chloride andextracted with AcOEt. The combined extracts are washed with brine, driedover sodium sulfate and concentrated under vacuum to give 402 mg ofcrude product, which is purified by silica gel column chromatography toafford the title compound. Yield: 85%. Rf=0.3 (AcOEt only)

¹H NMR(400 MHz, CDCl₃) δ 0.98(s, 9H), 1.46(s, 9H), 2.56 (t, 4H), 3.37(d,2H), 3.49(t, 4H), 3.64(s, 2H), 5.74-5.84(m, 1H), 8.20(s, 1H)

B.4-(2,2-Dimethyl-propylamino)-5-(3-piperazin-1-yl-prop-1-ynyl)-pyrimidine-2-carbonitrile

To a solution of4-{3-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-yl]-prop-2-ynyl}-piperazine-1-carboxylicacid .tert.-butyl ester (2.9 mmol) in dioxane (5 ml), 4Nhydrogenchloride in dioxane(15 ml) is added at 0° C. The reactionmixture is stirred at room temperature for 1 day and then evaporatedunder reduced pressure. To a solution of residual solid, CH₂Cl₂ is addedat room temperature, pH is adjusted to 9.0 by triethylamine. The mixtureis quenched with ammonium chloride and extracted with CH₂Cl₂. Thecombined extracts are washed with brine, dried over sodium sulfate andconcentrated under vacuum. The residue is purified by silica gel columnchromatography to afford title compound in 72% yield. Rf=0.11(MeOH:CH₂C₂=1:9)

¹H NMR(400 MHz, CDCl₃) δ 0.98(s, 9H), 2.6-2.7(m, 4H), 2.9-3.0 (m, 4H),3.38(d, 2H), 3.62(s, 2H), 5.75-5.82(m, 1H), 8.22(s, 1H)

C.5-{3-[4-(3-Chloro-propane-1-sulfonyl)-piperazin-1-yl]-prop-1-ynyl}-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile

To a solution of4-(2,2-dimethyl-propylamino)-5-(3-piperazin-1-yl-prop-1-ynyl)-pyrimidine-2-carbonitrile(0.16 mmol) in CH₂Cl₂ (5 ml), 3-chloropropanesulfonyl chloride (0.192mmol) and triethylamine (0.192 mmol) are added at 0° C. The reactionmixture is stirred at room temperature for 14 h and then saturatedaqueous solution of ammonium chloride is added to the reaction mixture.The mixture is extracted with two 50 ml portions of AcOEt. The combinedextracts are washed with brine, dried over sodium sulfate andconcentrated under vacuum. The purification of the residue by silica gelcolumn chromatography affords 37 mg of title compound in 51% yield.Rf=0.33(AcOEt only)

¹H NMR(400 MHz CDCl₃) δ 0.98(s, 9H), 2.25-2.35(m, 2H), 2.71 (t, 4H),3.10(t, 3H), 2H), 3.68(s, 2H), 3.69(t, 3H), 5.75(m, 1H), 8.22(s, 1H)

By repeating the procedures described in the above example usingappropriate starting materials and conditions the following compounds offormula 12-5 are obtained as identified below in Table 2-5. TABLE 12-512-5

Expl. No. R Yield (%) Rf (Solvent) ¹H NMR(400 MHz, δ) 12-20

31 0.60 (AcOEt only) (CDCl₃): 0.97(s, 9H), 2.70(t, 4H), 3.04-3.12(m,4H), 3.37(d, 2H), 3.60(s, 2H), 3.87(s, 3H), 5.70-5.78(m, 1H), 7.00(d,2H), 7.70(d, 2H), 8.19(s, 1H) 12-21

71 0.67 (MeOH:CH₂Cl₂ = 1:19) (CDCl₃): 0.97(s, 9H), 2.62(t, 4H), 3.00(s,6H), 3.38(d, 2H), 3.66(s, 2H), 3.69-3.75(m, 4H), 5.75-5.81(m, 1H),6.67(d, 2H), 7.35(d, 2H), 8.21(s, 1H) 12-22

79 0.16 (AcOEt only) (CDCl₃): 0.97(s, 9H), 2.24(s, 3H), 2.68(t, 4H),3.05-3.15(m, 4H), 3.37(d, 2H), 3.60(s, 2H), 5.68-5.76(m, 1H), 7.70(m,4H), 8.17(s, 1H) 12-19

51 0.33 (AcOEt only) (CDCl₃): 0.98(s, 9H), 2.25-2.35(m, 2H), 2.71(t,4H), 3.10(t, 3H), 3.35-3.42(m, 4H), 3.38(d, 2H), 3.68(s, 2H), 3.69(t,3H), 5.75(m, 1H), 8.22(s, 1H)

12-235-[3-(4-Benzyl-2,6-dioxo-piperazin-1-yl)-prop-1-ynyl]-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile

A. 4-Benzyl-1-prop-2-ynyl-piperazine-2,6-dione

To a suspension of N-benzyliminodiacetic acid (10 mmol) in THF (30 ml),1,1′-carbonyldiimidazole (22 mmol) is added with stirring. The reactionmixture is refluxed with stirring for 15 minutes. Propargylamine (100mmol) is added and then reaction mixture is stirred at 90° C. for 1 day.The organic solvent is evaporated and then the residue is dissolved inAcOEt. The organic layer is washed with 2×100 ml 0.1N HCl and then driedover sodium sulfate. The solvent is concentrated under vacuum. Thepurification of the residue by silica gel column chromatography affords1.5 g of title compound in 62% yield. Rf=0.24 (n-hexane:AcOEt=3:1)

B.5-[3-(4-Benzyl-2,6-dioxo-piperazin-1-yl)-prop-1-ynyl]-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile

To a solution of 4-benzyl-1-prop-2-ynyl-piperazine-2,6-dione (1.5 mmol)and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (1mmol) in DMF (5 ml), triethylamine (3.0 mmol),dichlorobis(triphenylphosphine)palladium (II) (0.1 mmol) and copper (I)iodide (0.2 mmol) are added. The reaction mixture is heated at 85° C.ca. for 1 day. Saturated aqueous solution of ammonium chloride is addedto the reaction mixture and then aqueous layer is extracted with two 50ml portions of AcOEt. The combined extracts are washed with brine, driedover magnesium sulfate and concentrated under vacuum to give crudeproduct, which is purified by silica gel column chromatography. Yield:93%. Rf=0.3 (AcOEt only)

¹H NMR(400 MHz, CDCl₃) δ 0.96(s, 9H), 3.36(d, 2H), 3.46(s, 4H), 3.65(s,2H), 4.77(s, 2H), 6.02-6.04(m, 1H), 7.27(d, 2H), 7.34(t, 3H), 8.16(s,1H)

Example 13 describes the preparation of substituted4-amino-pyrimidine-2-carbonitriles

Example 13-14-[{4-[3-(4-Acetyl-piperazin-1-yl)-prop-1-ynyl]-benzyl}-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

A) (2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine

2,4-Dichloropyrimidine (25 g, 0.16 moles) and 2,2-dimethyl-propylamine(25 ml, 0.21 moles) are dissolved in 250 ml of THF and K₂CO₃ (33.1 g,0.24 mmoles) is added at rt. The mixture is refluxed at rt for 8 h.Water is added and the organic layer is extracted with AcOEt, washedwith brine, dried over magnesum sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give 22 g ofdesired (2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 67%yield.

¹H NMR (400 MHz, CDCl₃) δ 0.98 (s, 9H), 3.02 (brs, 2H), 5.15 (brs, 1H),6.25 (d, 1H), 8.03 (brs, 2H)

Rf=0.32 (n-Hexane:AcOEt=1:1)

B) (2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine

13-1A (4.8 g, 24.0 mmoles) and 1-bromomethyl-4-iodo-benzene (8.6 g, 28.5mmoles) are dissolved in 25 ml of DMF and NaH (1.6 g, 40.9 mmoles, 60%oil suspenstion) is added at 0° C. The mixture is stirred at rt for 4 h.Water is added and the organic layer is extracted with AcOEt, washedwith brine, dried over magnesum sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give 10.1 gof desired(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine in100% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.01 (s, 9H), 3.44 (brs, 2H), 4.77 (brs, 2H),6.30 (brs, 11), 6.88 (d, 2H), 7.65 (d, 2H), 7.97 (d, 2H)

Rf=0.50 (n-Hexane:AcOEt=1:1)

C)4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile

(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine(10.0 g, 24.0 mmoles) and sodium cyanide (5.6 g, 0.12 moles) aredissolved in 40 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (0.27 g,2.4 mmoles) is added at rt. The mixture is stirred at 75° C. for 21 h.Water is added and the organic layer is extracted with AcOEt, washedwith brine, dried over magnesum sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give 8.4 g ofdesired4-[(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrilein 86% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.01 (s, 9H), 3.32 (brs, 2H), 4.75 (brs, 2H),6.46 (brs, 1H), 6.99 (d, 2H), 7.69 (d, 2H), 8.27 (brs, 2H)

Rf=0.50 (n-Hexane:AcOEt)=1:1

D)4-{(2,2-Dimethyl-propyl)-[4-(3-hydroxy-prop-1-ynyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

13-1C (8.4 g, 20.7 mmoles), prop-2-yn-1-ol (3.6 ml, 62.0 mmoles), CuI(0.4 g, 2.1 mmol) and ethyl-diisopropyl-amine (17.8 ml, 1.1 moles) aredissolved in 100 ml of DMF and Pd(PPh₃)₂Cl₂ (0.7 g, 1.1 mmoles) is addedat rt. The mixture is stirred at rt for 1 h. Water is added and theorganic layer is extracted with AcOEt, washed with brine, dried overmagnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give 6.1 g of desired4-{(2,2-dimethyl-propyl)-[4-(3-hydroxy-prop-1-ynyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein 82% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.03 (s, 9H), 1.69 (t, 1H), 3.65 (brs, 2H),4.43 (d, 2H), 4.79 (brs, 2H), 6.48 (brs, 1H), 7.18 (d, 2H), 7.43 (d,2H), 8.11 (brs, 2H)

Rf=0.29 (n-Hexane:AcOEt=1:1)

E)4-[[4-(3-Chloro-prop-1-ynyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

13-1D (6.0 g, 18.1 mmoles) and ethyl-diisopropyl-amine (15.7 ml, 90.7mmoles) are dissolved in 120 ml of dichloromethane and methansulfonylchloride (3.5 ml, 45.3 mmoles) is added at 0° C. The mixture is stirredat rt for overnight. Water is added and the organic layer is extractedwith dichloromethane, dried over magnesum sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to give5.4 g of desired4-[[4-(3-chloro-prop-1-ynyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrilein 85% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 3.65 (brs, 2H), 4.36 (s, 2H),4.81 (brs, 2H), 6.45 (brs, 1H), 7.06 (d, 2H), 7.40 (d, 2H), 8.11 (brs,2H)

Rf=0.65 (n-Hexane:AcOEt=1:1)

F)4-[{4-[3-(4-Acetyl-piperazin-1-yl)-prop-1-ynyl]-benzyl}-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

13-1E (70 mg, 0.20 mmoles) is dissolved in 3 ml of DMF and1-piperazin-1-yl-ethanone (50.1 mg, 0.40 mmoles) is added at rt. Themixture is stirred at rt for overnight. Water is added and the organiclayer is extracted with AcOEt, dried over magnesum sulfate andconcentrated. The crude product is purified by silica gel columnchromatography to give 67 mg of desired4-[{4-[3-(4-acetyl-piperazin-1-yl)-prop-1-ynyl]-benzyl}-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrilein 75% yield.

By repeating the procedure described above using appropriate startingmaterial and conditions the following compounds of formula 13-1 areobtained as identified below in Table 13-1. TABLE 13-1 13-1

Expl. No R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-1

75 0.50 (MeOH:CH₂Cl₂ = 1:5) 1.02(s, 9H), 2.10(s, 3H), 2.60(pent, 4H),3.52(t, 2H), 3.54(s, 2H), 3.68(t, 2H), 4.79(brs, 2H), 6.47(brs, 1H),7.03(d, 2H), 7.37(d, 2H), 8.19(brs, 2H) 13-2

90 0.19 (AcOEt:MeOH = 9:1) 1.02(s, 9H), 2.56-2.66(m, 4H), 3.44(t, 2H),3.55(s, 2H), 3.62(t, 2H), 3.68(brs, 2H), 4.86(br, 2H), 6.47(br, 1H),7.04(d, 2H), 7.37(d, 2H), 8.03(s, 1H), 8.10(s, 1H) 13-3

88 0.34 (MeOH:CH₂Cl₂ = 1:10) 1.02(s, 9H), 1.35-1.46(m, 2H), 1.49-1.68(m,4H), 2.55(brs, 4H), 3.49(s, 2H), 3.65(brs, 2H), 4.79(brs, 2H), 6.37(brs,1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(s, 1H) 13-4

52 0.21 (MeOH) 1.02(s, 9H), 2.31(s, 3H), 2.51(brs, 4H), 2.67(brs, 4H),3.51(s, 2H), 3.57(brs, 2H), 4.80(brs, 2H), 6.40(brs, 1H), 7.03(d, 2H),7.37(d, 2H), 8.10(br, 1H) 13-5

51 0.17 (AcOEt:MeOH = 91:1) 1.02(s, 9H), 1.83(brs, 4H), 2.69(brs, 4H),3.57(brs, 2H), 3.62(s, 2H), 4.82(brs, 2H), 6.45(br, 1H), 7.03(d, 2H),7.37(d, 2H), 8.10(br, 1H) 13-6

45 0.05 (MeOH) 1.02(s, 9H), 1.76-1.92(m, 2H), 2.40(s, 3H), 2.78(brs,4H), 2.78-2.89(m, 4H), 3.57(s, 2H), 3.59(brs, 2H), 4.78(brs, 2H),6.39(brs, 1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(brs, 1H) 13-7

90 0.15 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.59-1.64(m, 4H), 1.69-1.74(m,4H), 2.74(t, 4H), 3.57(s, 2H), 3.59(brs, 2H), 4.79(brs, 2H), 6.39(brs,1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(brs, 1H) 13-8

90 0.35 (MeOH:CH₂Cl₂ = 1:2) 1.02(s, 9H), 1.25-1.78(m, 10H), 1.80-1.99(m,1H), 2.25(t, 2H), 2.57(brs, 4H), 3.04(d, 2H), 3.49(s, 2H), 3.66(brs,2H), 4.75(brs, 2H), 6.58(brs, 1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(brs,1H) 13-9

85 0.05 (MeOH) 1.02(s, 9H), 1.55-1.68(m, 2H), 1.75-1.83(m, 4H),1.90-2.03(m, 2H), 2.28(t, 2H), 2.55-2.63(m, 4H), 2.94(d, 2H), 3.49(s,2H), 3.30-3.85(m, 3H), 4.79(br, 2H), 6.394(br, 1H), 7.03(d, 2H), 7.38(d,2H), 8.10(s, 1H) 13-10

69 0.10 (AcOEt:MeOH = 5:1) 1.02(s, 9H), 1.10(t, 3H), 2.45(q, 2H),2.33-2.89(m, 8H), 3.57(s, 2H), 3.66(brs, 2H), 4.78(brs, 2H), 6.39(brs,1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(brs, 1H) 13-11

92 0.07 (AcOEt:MeOH = 5:1) 1.02(s, 9H), 1.05(d, 6H), 2.58-2.82(m, 9H),3.50(s, 2H), 3.67(brs, 2H), 4.78(brs, 2H), 6.44(brs, 1H), 7.03(d, 2H),7.37(d, 2H), 8.10(s, 1H) 13-12

68 0.23 (AcOEt) 1.02(s, 9H), 1.38(t, 3H), 2.70(t, 4H), 2.96(q, 2H),3.38(t, 4H), 3.55(s, 2H), 3.66(brs, 2H), 4.78(brs, 2H), 6.39(brs, 1H),7.03(d, 2H), 7.37(d, 2H), 8.10(brs, 1H) 13-13

88 0.20 (AcOEt) 1.02(s, 9H), 1.48-1.58(m, 1H), 1.59-1.72(m, 2H),1.92-2.02(m, 2H), 2.40(t, 2H), 2.88-2.93(m, 2H), 3.49(s, 2H),3.52-3.82(m, 3H), 4.79(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H), 7.37(d,2H), 8.10(s, 1H) 13-14

77 0.50 (AcOEt) 1.02(s, 9H), 2.52(t, 4H), 2.97(t, 4H), 3.49(brs, 2H),3.64(s, 2H), 4.79(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H), 7.37(d, 2H),8.10(s, 1H) 13-15

83 0.19 (AcOEt) 1.02(s, 9H), 1.07-1.41(m, 6H), 1.58-1.66(m, 1H),1.72-1.81(m, 2H), 1.88-1.95(m, 2H), 2.67-2.76(m, 1H), 2.40(t, 2H),3.46(brs, 2H), 3.66(s, 2H), 4.76(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H),7.37(d, 2h), 8.10(s, 1H) 13-16

11 0.45 (AcOEt) 1.02(s, 9H), 1.40-1.83(m, 7H), 2.52-2.63(m, 4H), 3.49(s,2H), 3.66(brs, 2H), 4.76(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H), 7.37(d,2H), 8.10(s, 1H) 13-17

52 0.25 (MeOH:CH₂Cl₂ = 1:3) 1.02(s, 9H), 1.26-1.38(m, 1H), 1.42-1.63(m,4H), 1.77(d, 2H), 2.22(t, 2H), 2.59(d, 2H), 3.00(d, 2H), 3.49(s, 2H),3.63(brs, 2H), 4.79(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H), 7.37(d, 2H),8.10(s, 1H), 13-18

33 0.01 (AcOEt) 1.02(s, 9H), 1.78-2.28(m, 5H), 2.38-2.46(m, 2H),2.98-3.04(m, 2H), 3.54(s, 2H), 3.63(brs, 2H), 4.79(brs, 2H), 6.37(brs,1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(s, 1H), 10.05(brs, 1H) 13-19

63 0.05 (AcOEt) 1.02(s, 9H), 1.27-1.38(m, 2H), 1.47-1.62(m, 2H) 1.77(d,2H), 2.26(t, 2H), 3.01(d, 2H), 3.54(s, 2H), 3.41-3.59(m, 2H), 3.63(brs,2H), 4.79(brs, 2H), 6.37(brs, 1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(s, 1H)13-20

68 0.11 (MeOH) 1.02(s, 9H), 1.59(brs, 1H), 2.46(t, 4H), 2.52(t, 2H),2.84(t, 2H), 3.44(brs, 2H), 3.66(s, 2H), 3.70(t, 4H), 4.80(brs, 2H),6.37(brs, 1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(s, 1H) 13-21

78 0.14 (MeOH) 1.02(s, 9H), 1.32-1.64(m, 7H), 2.27-2.43(m, 4H), 2.47(t,2H), 2.83(t, 2H), 3.49(s, 2H), 3.66(brs, 2H), 4.80(brs, 2H), 6.37(brs,1H), 7.03(d, 2H), 7.37(d, 2H), 8.10(s, 1H) 13-22

100 0.36 (AcOEt:MeOH = 9:1) 1.02(s, 9H), 3.52(brs, 2H), 4.82(brs, 2H),4.94(s, 2H), 6.46(brs, 1H), 7.06-7.14(m, 4H), 7.39(d, 2H), 7.64(s, 1H),8.11(s, 1H) 13-23

64 0.40 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 3.65(brs, 1H), 4.89(brs, 2H),5.20(s, 1H), 6.57(brs, 1H), 7.08(d, 2H), 7.42(d, 2H), 7.98(s, 1H),8.12(s, 1H), 8.33(s, 1H) 13-24 —NH₂ 62 0.07(AcOEt:MeOH = 9:1) 1.02(s,9H), 1.36-1.45(m, 2H), 3.50, (brs, 2H), 3.63(d, 2H), 4.93(brs, 2H),6.39(br, 1H), 7.03(d, 2H), 7.35(d, 2H), 8.10(s, 1H)

13-251-[3-(4-{[(2-Cyano-pyrimidin-4yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-prop-2-ynyl]-piperidine-4-carboxylicacid [1,2,4]triazol-4-ylamide

13-18 (56 mg, 0.13 mmoles) and 4-amino-1,2,4-triazole (21 mg, 0.25mmoles) are dissolved in 3 ml of DMF and HOBT (36 mg, 0.26 mmoles) andWSCD (34 mg, 0.18 mmoles) are added at 0° C. The mixture is stirred atrt for overnight. Water is added and the organic layer is extracted withAcOEt, dried over magnesum sulfate and concentrated. The crude productis purified by silica gel column chromatography to give 56 mg of desired1-[3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-prop-2-ynyl]-piperidine-4-carboxylicacid [1,2,4]triazol-4-ylamide in 56% yield.

By repeating the procedure described above using appropriate startingmaterial and conditions the following compounds of formula 13-2 areobtained as identified below in Table 13-2. TABLE 13-2 13-2

Expl. No R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-25

56 0.45 (CH₂Cl₂:MeOH = 4:1) 1.02(s, 9H), 1.91-2.07(m, 4H), 2.31-2.48(m,3H), 3.01-3.29(m, 2H), 3.49(s, 1H), 3.53(s, 2H), 3.69(brs, 2H),4.80(brs, 2H), 6.57(brs, 1H), 7.04(d, 2H), 7.39(d, 2H), 8.12(s, 3H)13-26

76 0.43 (AcOEt:MeOH = 5:1) 1.02(s, 9H), 1.10(t, 3H), 1.19(t, 3H),1.89-2.20(m, 2H), 2.23-2.43(m, 3H), 3.01(d, 2H), 3.34(q, 2H), 3.37(q,2H), 3.52(s, 2H), 3.66(brs, 2H), 4.80(brs, 2H), 6.57(brs, 1H), 7.04(d,2H), 7.39(d, 2H), 8.10(s, 1H)

13-274-{(2,2-Dimethyl-propyl)-[2-fluoro-4-(3-piperidin-1-yl-prop-1-ynyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

By repeating the procedure described in Example 11-1 using appropriatestarting material and conditions the following compounds of formula 13-3are obtained as identified below in Table 13-3. TABLE 13-3 13-3

Expl. No R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-27

61 0.12 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.39-1.52(m, 2H), 1.59-1.68(m,4H), 2.47-2.52(m, 4H), 3.45(s, 2H), 3.66(brs, 2H), 4.83(br, 2H),6.57(br, 1H), 6.81-7.08(m, 1H), 7.09-7.15(m, 2H), 8.12(s, 1H) 13-28

92 0.28 (AcOEt:MeOH = 1:1) 1.02(s, 9H), 1.39(brs, 1H), 1.61-1.73(m, 2H),1.91-2.02(m, 2H), 2.39(t, 2H), 2.81-2.90(m, 2H), 3.23-3.82(m, 3H),3.49(s, 2H), 4.84(br, 2H), 6.66(brs, 1H), 6.89-7.13(m, 3H), 8.13(d, 1H)

13-294-[(2,2-Dimethyl-propyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-pyrimidine-2-carbonitrile

By repeating the procedures described in Examples 13-1-B and 13-1-Cusing appropriate starting material and conditions, the followingcompounds of formula 13-4 are obtained as identified below in Table13-4. TABLE 13-4 13-4

Expl. No R Yield (%) Rf (solvent) ¹H NMR (400 MHz, CDCl3, δ) 13-30

38 0.50 (MeOH:CH₂Cl₂ = 1:9) 1.05(s, 9H), 3.48(brs, 2H), 4.90(brs, 2H),6.57(brs, 1H), 7.23(d, 2H), 7.25(brs, 1H), 7.36(d, 2H), 8.10(s, 1H),8.15(brs, 2H) 13-29

91 0.45 (AcOEt) 1.05(s, 9H), 3.48(brs, 2H), 4.89(brs, 2H), 6.51(brs,1H), 7.25(d, 2H), 7.63(d, 2H), 8.07(s, 1H), 8.10(s, 1H), 8.53(s, 1H)13-31 —CH═CH₂ 59 0.40 1.02(s, 9H), 3.64(brs, (AcOEt:Hexane = 1:2) 2H),4.76(brs, 2H), 5.26(t, 1H), 5.72(d, 1H), 6.48(brs, 1H), 6.68(dd, 1H),7.06(d, 2H), 7.35(s, 2H), 8.09(s, 1H)

13-324-{(2,2-Dimethyl-propyl-[4-(3-methyl-3H-imidazol-4-yl)-benzyl]-amino}-pyrimidine-2-carbonitrile

4-{(2,2-Dimethyl-propyl)-[4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile(200 mg, 0.5 mmoles), 1-methyl imidazole (0.2 ml, 2.5 mmoles),triphenylphosphine (26 mg, 0.10 mmoles) and CsCO3 (160 mg, 0.5 mmoles)are dissolved in 3 ml of DMF and Pd(OAc)2 (10 mg, 0.05 mmoles) is addedat rt. The mixture is stirred at 120° C. for 18 h. Water is added andthe organic layer is extracted with AcOEt, washed with brine, dried overmagnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give 104 mg of desired4-{(2,2-dimethyl-propyl)-[4-(3-methyl-3H-imidazol-4-yl)-benzyl]-amino}-pyrimidine-2-carbonitrilein 59% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 3.47 (brs, 2H), 3.66 (s, 3H),4.87 (brs, 2H), 6.49 (brs, 1H), 6.97 (brs, 1H), 7.18 (d, 2H), 7.35 (d,2H), 7.52 (s, 1H), 8.14 (brs, 2H), Rf=0.07 (AcOEt)

13-334-[(2,2-Dimethyl-propyl)-(4-oxazol-2-yl-benzyl)-amino]-pyrimidine-2-carbonitrile

To a solution of oxazole (0.5 ml, 7.2 mmoles) in 10 ml of THF at −78° C.is added BuLi (5.23 ml, 8.0 mmoles, 1.6 M solution in hexane). After 30min, ZnCl2 (3.0g, 21.7 mmoles) and then a solution of4-{(2,2-Dimethyl-propyl)-(4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile(2.9 g, 7.2 mmoles) in 10 ml of THF are added. The reaction mixture iswarmed to 0° C. for 1 h. The reaction mixture is added to Pd(PPh₃)₄ (0.9g, 0.8 mmoles) and heated to reflux. Water is added and is filteredthrough a pad of Celite which is wshed with AcOEt. The organic layer isextracted with AcOEt, washed with brine, dried over magnesum sulfate andconcentrated. The crude product is purified by silica gel columnchromatography to give 104 mg of desired4-[(2,2-dimethyl-propyl)-(4-oxazol-2-yl-benzyl)-amino]-pyrimidine-2-carbonitrilein 16% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.04 (s, 9H), 3.64 (brs, 2H), 4.87 (brs, 2H),6.54 (brs, 1H), 7.20 (d, 2H), 7.23 8s, 1H), 7.78 (s, 1H), 8.00 (d, 2H),8.12 (brs, 1H)

Rf=0.12 (AcOEt:Hexane=1:2)

13-34 4-[(2,2-Dimethyl-propyl)-(4-[12,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrile

A)(4-Bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine

(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (2.0 g, 10.0mmoles) and 1,4-bis-bromomethyl-benzene (4.0 g, 15.0 mmoles) aredissolved in 50 ml of DMF and NaH (0.8 g, 21.0 mmoles, 60% oilsuspenstion) is added at 0° C. The mixture is stirred at rt forovernight. Water is added and the organic layer is extracted with AcOEt,washed with brine, dried over magnesum sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to give0.9 g of desired(4-bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-aminein 24% yield.

Rf=0.76 (n-Hexane:AcOEt=1:1)

B)(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amine

(4-Bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine(0.2 g, 0.5 mmoles) obtained above and 1,2,4-triazole (72 mg, 1.1mmoles) are dissolved in 5 ml of DMF and NaH (44 mg, 1.1 mmoles, 60% oilsuspenstion) is added at 0° C. The mixture is stirred at rt forovernight. Water is added and the organic layer is extracted with AcOEt,washed with brine, dried over magnesum sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to give160 mg of desired(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-aminein 100% yield.

Rf=0.92, (CH₂Cl₂:MeOH=1:9)

C)4-[(2,2-Dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrile

(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amine(160 mg, 0.43 mmoles) and sodium cyanide (0.1 g, 2.2 mmoles) aredissolved in 5 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (23 mg, 0.2mmoles) is added at rt. The mixture is stirred at rt for 5 h at 70° C.Water is added and the organic layer is extracted with AcOEt, washedwith brine, dried over magnesum sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give 50 g ofdesired4-[(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrilein 32% yield.

By repeating the procedures described in Examples 13-34-B and 13-34-Cusing appropriate starting material and conditions, the followingcompounds of formula 13-5 are obtained as identified below in Table13-5. TABLE 13-5 13-5

Expl. No. R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-35

43 0.27 (AcOEt:MeOH = 9:1) 1.02(s, 9H), 3.49(brs, 2H), 4.77(bsr, 2H),5.10(s, 2H), 6.49(br, 1H), 6.90(s, 1H), 7.08-7.17(m, 5H), 7.54(s, 1H),8.12(s, 1H) 13-34

32 0.52 (AcOEt:MeOH = 9:1) 1.02(s, 9H), 3.49(brs, 2H), 4.89(brs, 2H),5.32(s, 2H), 6.54(brs, 1H), 7.11(d, 2H), 7.22(d, 2H), 7.97(s, 1H),8.07(s, 1H), 8.11(s, 1H)

13-364-[(2,2-Dimethyl-propyl)-(4-ethyl-benzyl)-amino]-pyrimidine-2-carbonitrile

A)4-[(2,2-Dimethyl-propyl)-(4-ethynyl-benzyl)-amino]-pyrimidine-2-carbonitrile

At room temperature, a soln. of4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile(2 g, 4.9 mmoles) and ethynyl-trimethyl-silane (3.47 ml, 24.7 mmoles) in20 ml of DMF is treated with triethylamine (2.6 ml, 14.8 mmoles), CuI(93 mg, 0.5 mmoles) and (Ph₃P)₂PdCl₂ (0.2 g, 0.2 mmoles). The mixture isstirred at rt for overnght. Water is added and the organic layer isextracted with AcOEt, washed with brine, dried over magnesum sulfate andconcentrated. The crude product is purified by silica gel columnchromatography to give 6.1 g of desired4-[(2,2-dimethyl-propyl)-(4-trimethylsilanylethynyl-benzyl)-amino]-pyrimidine-2-carbonitrilein 82% yield. Rf=0.52 (Hexane:AcOEt=1:1)

The crude product is dissolved in 30 ml of MeOH and 10 ml of water andCsF (0. 5g, 3.0 mmoles) is added at rt and the mixture is stirred at rtfor 2 h. The reaction mixture is evaporated, then water anddichloromethane are added. The organic layer is washed with brine, driedover magnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give4-[(2,2-dimethyl-propyl)-(4-ethynyl-benzyl)-amino]-pyrimidine-2-carbonitrilein 97% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 3.07 (s, 1H), 3.64 (brs, 2H),4.81 (brs, 2H), 6.46 (brs,1H), 7.06 (d, 2H), 7.44 (d, 2H), 8.12 (s, 1H)

Rf=0.36 (Hexanes:AcOEt=2:1)

B4-[(2,2-Dimethyl-propyl)-(4-ethyl-benzyl)-amino]-pyrimidine-2-carbonitrile

4-[(2,2-Dimethyl-propyl)-(4-ethynyl-benzyl)-amino]-pyrimidine-2-carbonitrile(47 mg, 0.11 mmoles) is dissolved in 5 ml of EtOH and 10% Pd—C (5 mg) isadded at rt. The mixture is stirred under hydrogen at rt for overnightand is filtered through a pad of Celite which is washed with EtOH. Thefiltrate is concentrated and the crude product is purified by silica gelcolumn chromatography to give 38 mg of desired4-[(2,2-dimethyl-propyl)-(4-ethyl-benzyl)-amino]-pyrimidine-2-carbonitrilein 77% yield.

¹H NMR(400 MHz, CDCl₃) δ 1.02 (s, 9H), 1.21 (t, 3H), 2.62 (q, 2H), 3.67(brs, 2H), 4.73 (brs,2H), 6.43 (brs, 1H), 7.01 (d, 2H), 7.14 (d, 2H),8.08 (brs, 1H)

Rf=0.80 (Hexanes:AcOEt=1:1)

13-364-[{4-[3-(4-acetyl-piperazin-1-yl)-propyl]-benzyl}-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

13-1 (47 mg, 0.11 mmoles) is dissolved in 5 ml of EtOH and 10% Pd—C (5mg) is added at rt. The mixture is stirred under hydrogen at rt forovernight and is filtered through a pad of Celite which is washed withEtOH. The filtrate is concentrated and the crude product is purified bysilica gel column chromatography to give 38 mg of desired4-[{4-[3-(4-acetyl-piperazin-1-yl)-propyl]-benzyl}-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrilein 80% yield.

By repeating the procedures described in Examples 13-1-F and 13-37 usingappropriate starting material and conditions, the following compounds offormula 13-6 are obtained as identified below in Table 13-6. TABLE 13-613-6

Example No. R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-37

80 0.51 (MeOH:CH₂Cl₂ = 1:5) 1.02(s, 9H), 1.79(pent, 2H), 2.08(s, 3H),2.31-2.49(m, 6H), 2.62(t, 2H), 3.49(t, 2H), 3.61(t, 2H), 3.76(brs, 2H),4.76(br, 2H), 6.48(br, 1H), 7.00(d, 2H), 7.12(d, 2H), 8.09(s, 1H) 13-38

75 0.20 (AcOEt) 1.02(s, 9H), 1.37(t, 3H), 1.77(pent, 2H), 2.39(t, 2H),2.50(t, 4H), 2.92(q, 2H), 3.29(t, 4H), 3.66(brs, 2H), 4.76(br, 2H),6.49(br, 1H), 7.00(d, 2H), 7.12(d, 2H), 8.09(s, 1H) 13-39

84 0.16 (AcOEt) 1.02(s, 9H), 1.84(pent, 2H), 2.45-2.53(m, 6H), 2.65(t,2H), 2.73(t, 4H), 3.66(brs, 2H), 4.74(bsr, 2H), 6.54(brs, 1H), 7.01(d,2H), 7.14(d, 2H), 8.09(s, 1H)

13-404-((2,2-Dimethyl-propyl)-{4-[3-(4-hydroxyamino-piperidin-1-yl)-prop-1-ynyl]-benzyl}-amino)-pyrimidine-2-carbonitrile

13-39 (130 mg, 0.3 mmoles) and pyridine (0.05 ml, 0.6 mmoles) aredissolved in 5 ml of dichloromethane and hydroxylamine hydrochloride (52mg, 0.8 mmoles) is added at rt. The mixture is stirred at rt forovernight. Water is added and the organic layer is extracted with AcOEt,dried over magnesum sulfate and concentrated. The crude product ispurified by silica gel column chromatography to give 67 mg of4-((2,2-dimethyl-propyl)-{4-[3-(4-hydroxyamino-piperidin-1-yl)-prop-1-ynyl]-benzyl}-amino)-pyrimidine-2-carbonitrilein 52% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 1.81 (pent, 2H), 2.33 (t, 2H),2.37 (t, 2H), 2.51 (t, 2H), 2.54 (t, 2H), 2.61-2.65 (m, 4H), 3.89 (brs,2H), 4.74 (brs, 2H), 6.42 (brs, 1H), 6.82 (brs, 1H), 7.00 (d, 2H), 7.13(d, 2H), 8.08 (s, 1H)

Rf=0.33 (AcOEt:MeOH=9:1)

13-414-{(2,2-Dimethyl-propyl)-[4-(3-piperidin-1-yl-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileMethanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester

A)4-1(2,2-Dimethyl-propyl)-[4-(3-oxo-propyl)-benzyl]-amino)-pyrimidine-2-carbonitrile

B)4-{(2,2-Dimethyl-propyl)-[4-(1-methyl-2-oxo-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile(1.6 g, 3.8 mmoles), ally alcohol (0.3 ml, 4.8 mmoles), andtriethylamine (0.7 ml, 4.8 mmoles) are dissolved in 30 ml ofacetonitrile and Pd(OAc)₂ (43 mg, 0.19 mmoles) is added at rt. Themixture is stirred at 100° C. for 19 h. The reaction mixture isconcentrated and the crude residue is diluted with water. The organiclayer is extracted with dichloromethane, washed with brine, dried overmagnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give 672 mg of inseparable mixture4-{(2,2-dimethyl-propyl)-[4-(3-oxo-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileand4-{(2,2-dimethyl-propyl)-[4-(1-methyl-2-oxo-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein ratio of 3:1 in 52% yield.

Rf=0.60 (n-Hexane:AcOEt=1:1)

C)4-{(2,2-Dimethyl-propyl)-[4-(3-hydroxy-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileD)4-{(2,2-Dimethyl-propyl)-[4-(2-hydroxy-1-methyl-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

A mixture of4-{(2,2-dimethyl-propyl)-[4-(3-oxo-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileand4-{(2,2-dimethyl-propyl)-[4-(1-methyl-2-oxo-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrile(in ratio of 3:1) (672 mg, 2.0 mmoles) is dissolved in 15 ml of MeOH andNaBH₄ (76 mg, 2.0 mmoles) is added at 0° C. The mixture is stirred at 0°C. for 5 min. The reaction mixture is added 5 ml of acetone, andconcentrated. The cude residue is diluted with water and the organiclayer is extracted with dichloromethane, washed with brine, dried overmagnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give 432 mg of inseparable mixtureof4-{(2,2-dimethyl-propyl)-[4-(3-hydroxy-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileand4-{(2,2-dimethyl-propyl)-[4-(2-hydroxy-1-methyl-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein ratio of 3:1 in 64% yield.

Rf=0.38 (n-Hexane:AcOEt:=1:1)

E) Methanesulfonic acid3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester F) Methanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester

A mixture of4-{(2,2-dimethyl-propyl)-[4-(3-hydroxy-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileand4-{(2,2-dimethyl-propyl)-[4-(2-hydroxy-1-methyl-ethyl)-benzyl]-amino}-pyrimidine-2-carbonitrile(in ratio of 3:1) (430 mg, 1.3 mmoles) and ethyl-diisopropyl-amine (0.53ml, 3.1 mmoles) are dissolved in 10 ml of dichloromethane andmethansulfonyl chloride (0.12 ml, 1.5 mmoles) is added at 0° C. Themixture is stirred at rt for 2 h. Water is added and the organic layeris extracted with dichloromethane, dried over magnesum sulfate andconcentrated. The crude product is purified by silica gel columnchromatography to give 493 mg inseparable mixture of methanesulfonicacid3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl-phenyl)-propylester and methanesulfonic acid2-(4-([(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester in ratio of 3:1 in 93% yield.

Rf=0.75 (n-Hexane: AcOEt=1:1)

G)4-{(2,2-Dimethyl-propyl)-[4-(3-piperidin-1-yl-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrileH) Methanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester

A mixture of methanesulfonic acid3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester and methanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester (in ratio of 3:1) (130 mg, 0.31 mmoles) is dissolved in 3 ml ofDMF and 1-piperizine (0.06 ml, 0.64 mmoles) is added at rt. The mixtureis stirred at rt for overnight. Water is added and the organic layer isextracted with AcOEt, dried over magnesum sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to give 56mg of desired4-{(2,2-dimethyl-propyl)-[4-(3-piperidin-1-yl-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrile(A) in 56% yield and 24 mg of desired methanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester (B) in 18% yield.

Methanesulfonic acid2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propylester (B)

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 1.34 (d, 3H), 2.87 (s, 3H),3.18, (hex, 1H), 3.64 (brs, 2H), 4.22 (dd, 1H), 4.27 (dd, 1H), 4.76(bsr, 2H), 6.44 (brs, 1H), 6.46 (d, 1H), 7.07 (d, 2H), 7.19 (d, 2H),8.10 (s, 1H)

Rf=0.75 (n-Hexane: AcOEt=1:1)

By repeating the procedures described in Examples 13-41-G, H usingappropriate starting material and conditions, the following compounds offormula 13-7 are obtained as identified below in Table 13-7. TABLE 13-713-7

Example No. R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-41

56 0.10 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.38-1.46(m, 2H), 1.52-1.87(m,8H), 2.30-2.43(m, 4H), 2.65(t, 2H), 2.61(t, 2H), 3.66(brs, 2H),4.74(bsr, 2H), 6.54(brs, 1H), 7.01(d, 2H), 7.14(d, 2H), 8.09(s, 1H)13-42

69 0.05 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.51-1.68(m, 5H), 1.81(pent,2H), 1.87-1.93(m, 2H), 2.08-2.19(m, 2H), 2.35(t, 2H), 2.61(t, 2H),2.72-2.82(m, 2H), 3.66(brs, 2H, 2.69-78(m, 1H), 4.74(bsr, 2H), 6.54(brs,1H), 7.01(d, 2H), 7.14(d, 2H), 8.09(s, 1H) 13-43

11 0.10 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.28-1.35(m, 1H), 1.96(pent,2H), 2.08-2.29(m, 4H), 2.58-2.69(m, 4H), 3.06(t, 2H), 3.38-3.46(m, 2H),3.66(brs, 2H), 4.11(t, 2H), 4.74(bsr, 2H), 6.54(brs, 1H), 7.01(d, 2H),7.14(d, 2H), 8.09(s, 1H)

13-444-{(2,2-Dimethyl-propyl)-[4-((E)-3-piperidin-1-yl-propenyl)-benzyl]-amino})-pyrimidine-2-carbonitrile

A)4-{(2,2-Dimethyl-propyl)-[4-((E)-3-oxo-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile(1.3 g, 2.5 mmoles), acrolein (0.5 ml, 7.4 mmoles), and triethylamine(0.4 ml, 3.1 mmoles) are dissolved in 25 ml of acetonitrile and Pd(OAc)2(27 mg, 0.12 mmoles) is added at rt. The mixture is stirred at 80° C.for 18 h. Water is added and the organic layer is extracted with AcOEt,washed with brine, dried over magnesum sulfate and concentrated. Thecrude product is purified by silica gel column chromatography to give423 mg of desired4-{(2,2-dimethyl-propyl)-[4-((E)-3-oxo-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein 39% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 3.52 (brs, 2H), 4.79 (brs, 2H),6.69 (dd, 1H), 7.18 (d, 2H), 7.45 (d, 2H), 7.45 (d, 2H), 7.53 (d, 2H),8.14 (brs, 2H), 9.70 (d, 2H)

Rf=0.60, (n-Hexane:AcOEt)=1:1

B)4-{(2,2-Dimethyl-propyl)-[4-((E)-3-hydroxy-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

13-44A (423 mg, 1.3 mmoles) is dissolved in 5 ml of MeOH and NaBH4 (48mg, 1.3 mmoles) is added at 0° C. The mixture is stirred at 0° C. for 10min. The reaction mixture is added 5 ml of acetone, and concentrated.The crude residue is diluted with water and the organic layer isextracted with dichloromethane, washed with brine, dried over magnesumsulfate and concentrated. The crude product is purified by silica gelcolumn chromatography to give 342 mg of desired4-{(2,2-dimethyl-propyl)-[4-((E)-3-hydroxy-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein 80% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 1.44 (t, 1H), 3.47 (brs, 2H),4.32 (t, 2H), 4.78 (bsr, 2H), 6.35 (dt, 1H), 6.52 (brs, 1H), 6.59 (d,1H), 7.07 (d, 2H), 7.34 (d, 2H), 8.09 (s, 1H)

Rf=0.38 (AcOEt:Hexane=1:1)

C)4-[[4-((E)-3-Chloro-propenyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

13-44B (342 mg, 1.1 mmoles) and ethyl-diisopropyl-amine (0.42 ml, 2.4mmoles) are dissolved in 10 ml of dichloromethane and methansulfonylchloride (0.09 ml, 1.2 mmoles) is added at 0° C. The mixture is stirredat rt for 16 h. Water is added and the organic layer is extracted withdichloromethane, dried over magnesum sulfate and concentrated. The crudeproduct is purified by silica gel column chromatography to give 298 mgof desired4-[[4-(3-chloro-prop-1-enyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrilein 83% yield.

¹H NMR (400 MHz, CDCl₃) δ 1.02 (s, 9H), 3.47 (brs, 2H), 4.22 (d, 2H),4.80 (bsr, 2H), 6.30 (dt, 1H), 6.54 (brs, 1H), 6.62 (d, 1H), 7.07 (d,2H), 7.34 (d, 2H), 8.10 (s, 1H) Rf=0.84 (AcOEt:Hexane=1:1)

D)4-{(2,2-Dimethyl-propyl)-[4-((E)-3-piperidin-1-yl-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrile

13-44C (88 mg, 0.25 mmoles) is dissolved in 3 ml of DMF and 1-piperizine(0.05 ml, 0.50 mmoles) is added at rt. The mixture is stirred at rt forovernight. Water is added and the organic layer is extracted with AcOEt,dried over magnesum sulfate and concentrated. The crude product ispurified by silica gel column chromatography to give 61 mg of desired4-{(2,2-dimethyl-propyl)-[4-((E)-3-piperidin-1-yl-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrilein 61% yield.

By repeating the procedure described above using appropriate startingmaterial and conditions, the following compounds of formula 13-8 areobtained as identified below in Table 13-8. TABLE 13-8 13-8

Example No. R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-44

61 0.10 (AcOEt) 1.02(s, 9H), 1.38-1.46(m, 2H), 1.53-1.63(m, 4H),2.41-2.56(m, 4H), 3.10(d, 2H), 3.64(brs, 2H), 4.76(bsr, 2H), 6.30(dt,1H), 6.44(brs, 1H), 6.46(d, 1H), 7.07(d, 2H), 7.34(d, 2H), 8.10(s, 1H)13-45

57 0.29 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.98(pent, 2H), 2.67(t, 4H),3.64(brs, 2H), 4.32(d, 2H), 4.75(bsr, 2H), 6.17(dt, 1H), 6.37(brs, 1H),6.57(d, 1H), 7.02(d, 2H), 7.29(d, 2H), 8.08(s, 1H) 13-46

69 0.10 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 1.61(brt, 1H), 1.89-2.02(m,2H), 2.16-2.32(m, 2H), 2.79-2.90(m, 2H), 3.09-3.22(m, 2H), 3.46-3.89(m,3H), 4.76(bsr, 2H), 6.19-6.32(m, 2H), 6.48(d, 1H), 7.04(d, 2H), 7.32(d,2H), 8.09(s, 1H) 13-47

29 0.35 (MeOH:CH2Cl2 = 1:4) 1.02(s, 9H), 1.71-2.00(m, 3H), 2.12-2.28(m,2H), 2.81-3.21(m, 4H), 3.26(d, 2H), 3.65(brs, 2H), 4.76(bsr, 2H),6.19-6.32(m, 2H), 6.48(d, 1H), 7.04(d, 2H), 7.32(d, 2H), 8.06(s, 1H)13-48

48 0.10 (AcOEt) 1.02(s, 9H), 1.81(pent, 4H), 2.59(brs, 4H), 2.81-3.21(m,4H), 3.28(d, 2H), 3.59(brs, 2H), 4.76(bsr, 2H), 6.32(dt, 1H), 6.36(brs,1H), 6.50(d, 1H), 7.04(d, 2H), 7.32(d, 2H), 8.09(s, 1H) 13-49

96 0.33 (AcOEt:MeOH = 3:1) 1.02(s, 9H), 2.08(s, 3H), 2.46-2.55(m, 4H),3.16(d, 2H), 3.48(t, 2H), 3.64(t, 2H), 3.76(brs, 2H), 4.79(brs, 2H),6.23(dt, 1H), 6.41(brs, 1H), 6.49(d, 1H), 7.05(d, 2H), 7.32(d, 2H),8.09(s, 1H) 13-50

59 0.26 (MeOH) 1.02(s, 9H), 2.29(s, 3H), 2.38-2.67(m, 8H), 3.15(d, 2H),3.66(brs, 2H), 4.79(brs, 2H), 6.27(dt, 1H), 6.42(brs, 1H), 6.49(d, 2H),7.04(d, 2H), 7.31(d, 2H), 8.08(s, 1H) 13-51

83 0.07 (AcOEt:MeOH = 3:1) 1.02(s, 9H), 1.08(t, 3H), 2.42(q, 2H),2.53(bsr, 8H), 3.16(d, 2H), 3.60(br, 2H), 4.75(br, 2H), 6.26(dt, 1H),6.47(brs, 1H), 6.49(d, 1H), 7.04(d, 2H), 7.31(d, 2H), 8.08(s, 1H) 13-52

79 0.50 (AcOEt:MeOH = 9:1) 1.02(s, 9H), 1.37(t, 3H), 2.57(t, 4H),2.95(q, 2H), 3.18(d, 2H), 3.33(t, 4H), 3.63(brs, 2H), 4.77(brs, 2H),6.20(dt, 1H), 6.42(brs, 1H), 6.50(d, 1H), 7.06(d, 2H), 7.32(d, 2H),8.09(s, 1H) 13-53

73 0.10 (MeOH) 1.02(s, 9H), 1.38-1.69(m, 8H), 1.76-1.83(m, 2H), 2.04(t,2H), 2.22-2.32(m, 1H), 2.51(brt, 4H), 3.02(d, 2H), 3.11(d, 2H),3.66(brs, 2H), 4.76(brs, 2H), 6.27(dt, 1H), 6.44(brs, 1H), 6.46(d, 1H),7.03(d, 2H), 7.31(d, 2H), 8.08(s, 1H)

13-544-[[4-((E)-2-Cyano-vinyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile

4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile(0.1 g, 0.2 mmoles), acrolein (0.02 ml, 0.3 mmoles), and triethylamine(0.04 ml, 0.3 mmoles) are dissolved in 5 ml of acetonitrile and Pd(OAc)2(2.6 mg, 0.012 mmoles) is added at rt.

The mixture is stirred at 100° C. for overnight. Water is added and theorganic layer is extracted with AcOEt, washed with brine, dried overmagnesum sulfate and concentrated. The crude product is purified bysilica gel column chromatography to give 423 mg of desired4-[[4-((E)-2-cyano-vinyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrilein 45% yield.

By repeating the procedure described above using appropriate startingmaterial and conditions, the following compounds of formula 13-9 areobtained as identified below in Table 13-9. TABLE 13-9 13-9

Example No. R Yield (%) Rf (solvent) ¹H NMR(400 MHz, CDCl3, δ) 13-54 —CN45 0.56 (Hexane:AcOEt = 1:1) 1.03(s, 9H), 3.54(brs, 2H), 4.86(brs, 2H),5.85(d, 1H), 6.48(brs, 1H), 6.46(d, 1H), 7.15(d, 2H), 7.40(d, 2H),7.76(d, 1H), 8.14(s, 1H) 13-55

43 0.47 (AcOEt:MeOHe = 9:1) 1.02(s, 9H), 3.64(brs, 2H), 4.78(brs, 2H),4.95(d, 2H), 6.32(dt, 1H), 6.42(brs, 1H), 6.60(d, 1H), 7.07(d, 2H),7.33(d, 2H), 7.97(s, 1H), 8.10(brs, 1H), 8.12(s, 1H) 13-56

57 0.12 (AcOEt:Hexane = 1:1) 1.02(s, 9H), 3.64(brs, 2H), 4.78(br, 2H),5.16(d, 2H), 6.32(dt, 1H), 6.46(brs, 1H), 6.62(d, 1H), 7.07(d, 2H),7.33(d, 2H), 7.60(s, 1H), 7.73(s, 1H), 8.09(s, 1H)

1. compound of formula I, or a pharmaceutically acceptable salt or esterthereof

In which R is H, —R2,—OR2 or NR1R2, wherein R1 is H, lower alkyl or C₃to C₁₀ cycloalkyl, and R2 is lower alkyl or C₃ to C₁₀ cycloalkyl, andwherein R1 and R2 are independently, optionally substituted by halo,hydroxy, lower alkoxy, CN, NO₂, or optionally mono- or di-lower alkylsubstituted amino; X is ═N— or ═C(Z)-, wherein Z is H, —R4,—C≡C—CH₂—R5,C(P)═C(Q)-R3, wherein P and Q independently are H, lower alkyl or aryl,R3 is aryl, aryl-lower alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-loweralkyl, heterocyclyl or heterocyclyl-lower alkyl, wherein R3 isindependently, optionally substituted by one or more groups, e.g. 1-3groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO₂, oroptionally substituted (optionally mono- or di-lower alkyl substitutedamino, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-loweralkyl (wherein the optional substitution comprises from 1 to 3substituents selected from halo, hydroxy, lower alkoxy, CN, NO₂, oroptionally mono- or di-lower alkyl substituted amino)), R4 is H, aryl,aryl-lower alkyl, aryl-lower-alkenyl, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl,and wherein R5 is aryl, aryl-lower alkyl, aryloxy, aroyl orN-heterocyclyl as defined above, and wherein R5 is optionallysubstituted by R7 which represents from 1 to 5 substituents selectedfrom halo, hydroxy, CN, NO₂ or oxo, or optionally substituted(lower-alkoxy, lower-alkyl, aryl, aryloxy, aroyl, lower-alkylsulphonyl,arylsulphonyl, optionally mono- or di-lower alkyl substituted amino, orN-heterocyclyl, or N-heterocyclyl-lower alkyl, wherein N-heterocyclyldenotes a saturated, partially unsaturated or aromatic nitrogencontaining heterocyclic moiety attached via a nitrogen atom thereofhaving from 3 to 8 ring atoms optionally containing a further 1, 2 or 3heteroatoms selected from N, NR6, O, S, S(O) or S(O)2 wherein R6 is H oroptionally substituted (lower alkyl, carboxy, acyl (including both loweralkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl, e.g.benzoyl), amido, aryl, S(O) or S(O)₂), and wherein the N-heterocyclyl isoptionally fused in a bicyclic structure, e.g. with a benzene orpyridine ring, and wherein the N-heterocyclyl is optionally linked in aspiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ringwherein the heterocyclic ring has from 3 to 10 ring members and containsfrom 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O )₂wherein R6 is as defined above), and wherein heterocyclyl denotes a ringhaving from 3 to 10 ring members and containing from 1 to 3 heteroatomsselected from N, NR6, O, S, S(O) or S(O)₂ wherein R6 is as definedabove), and and wherein R7 is optionally substituted by from 1 to 3substituents selected from halo, hydroxy, optionally mono- or di-lower-alkyl substituted amino, lower-alkyl carbonyl, lower-alkoxy orlower-alkylamido; Y is —NR8R9, wherein R8 is H, or optionallysubstituted (lower alkyl, aryl, aryl-lower alkyl, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl),wherein R8 is optionally substituted by R10 which represents from 1 to 4substituents selected from halo, hydroxy, CN, NO₂, —O—C(O)—, optionallysubstituted (lower-alkyl, C₃-C₁₀cycloalkyl, lower-alkoxy, lower-alkenyl,lower-alkynyl, optionally mono- or di-lower alkyl-substituted amino orN-heterocyclyl (as defined above), wherein R10 is optionally substitutedby R11 which represents from 1 to 4 substituents selected from halo,hydroxy, CN, NO₂, oxo, optionally substituted (optionally mono- ordi-lower alkyl-substituted amino, lower alkyl, optionally-lower alkylsubstituted COOH, sulphinyl, sulphonyl, or N-heterocyclyl (as definedabove)) wherein R11 is optionally substituted by R12 which representsfrom 1 to 4 substituents selected from halo, hydroxy, CN, NO₂, oxo,hydroxy lower alkyl, C₃-C₁₀cycloalkyl, optionally loweralkyl-substituted carboxy, hydroximine, or N-heterocyclyl as definedabove, and wherein R9 is independently H, or optionally substituted(lower alkyl, aryl, aryl-lower alky, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl),and wherein R9 is optionally substituted by halo, hydroxy, oxo, loweralkoxy, CN, NO₂, or optionally mono- or di-lower alkyl substitutedamino; or Z and Y together with the carbon atoms to which they areattached are joined to provide a compound of formula I selected from,

wherein R is as defined above; R15 is lower-alkyl, C₃-C₁₀cycloalkyl,C₃-C₁₀cycloalkyl-lower alkyl, NR20R21-lower alkyl-, where T is —O— or adirect bond; R16 is NR20R21-lower alkyl- or R4, both as defined above,R20 is H, optionally substituted (lower alkyl, aryl, C₃-C₁₀cycloalkyl,lower alkoxy lower alkyl C₃-C₁₀cycloalkyl-lower alkyl or aryl loweralkyl), R21 is optionally substituted (lower alkyl, aryl,C₃-C₁₀cycloalkyl, lower alkoxy lower alkyl, C₃-C₁₀cycloalkyl-lower alkylor aryl-lower alkyl), or R20 and R21 form an N-heterocyclyl ring ashereinbefore defined, and wherein R20 or R21 are independentlyoptionally substituted by R23 which which represents from 1 to 3substituents selected from halo, hydroxy, CN, NO₂, oxo, optionally mono-or di-lower alkyl substituted amino, or optionally substituted(lower-alkoxy, lower-alkyl, lower alkoxy carbonyl, aryl, aryl-loweralkyl, aryl-lower alkenyl, aryloxy, aroyl, alkylsulphonyl, arylsulphonylor N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein N-heterocyclylis as defined above)); A is —CH═ or —C(O)—, B is —C═ or —N—, D is —CH═or —C(O)— and E is —CH═ or —N(R1) (where R1is as defined above).
 2. Acompound according to claim 1 of formula Ib, Ic, II, or IV or apharmaceutically acceptable salt or ester thereof

wherein R8′ is H or optionally substituted aryl-lower alkyl wherein R8′is optionally substituted as defined above for R8, and the other symbolsare as defined above.
 3. A compound according to claim 1 or apharmaceutically acceptable salt or ester thereof selected from acompound of formula VI, VII, VIII or IX

wherein the symbols are as defined above.
 4. A compound according toclaim 1, or a pharmaceutically acceptable salt or ester thereof,selected from any one of the Examples 1, 11,12,
 13. 5. A compoundaccording to claim 1 for use as a pharmaceutical.
 6. A pharmaceuticalcomposition comprising a compound according to claim 1 as an activeingredient.
 7. A method of treating a patient suffering from orsusceptible to a disease or medical condition in which cathepsin K isimplicated, comprising administering an effective amount of a compoundaccording to claim 1 to the patient.
 8. The use of a compound accordingto claim 1 for the preparation of a medicament for therapeutic orprophylactic treatment of a disease or medical condition in whichcathepsin K is implicated.
 9. A process for the preparation of acompound of formula I or a salt or ester thereof which comprises i) forthe preparation of compounds of formula VI or pharmaceuticallyacceptable salts or esters thereof

wherein R2 and R15 are as defined above, cyanation of a corresponding2-halo precursor of formula XI

wherein R2 and R15 are as defined above and Halo is preferably Cl; ii)for preparation of compounds of formula VII or pharmaceuticallyacceptable salts or esters thereof

wherein R2 and R16 are as defined above, coupling of a 6-hydroxyprecursor of formula XV with an R16-Halo precursor

wherein R2 and R16 are as defined above and Halo is preferably Cl; iii)for the preparation of compounds of formula VIII or pharmaceuticallyacceptable salts or esters thereof

wherein R2 and R5 are as defined above, coupling of a 5-halopyrimidineprecursor of formula XVI with a corresponding R5-CH₂—C≡CH propyne

wherein R2 and R5 are as defined above and Halo is preferably Br; iv)for the preparation of compounds of formula DC or pharmaceuticallyacceptable salts or esters thereof

wherein R2 is as defined above and R8″ is optionally substitutedaryl-lower alkyl as defined above for R8′, coupling of a secondary amineprecursor of formula XVII

wherein R2 is as defined above, with a corresponding R8″-Halo precursor,wherein Halo is preferably I; v) thereafter, if desired, converting theproduct obtained into a further compound of formula I, or into a salt orester thereof.
 10. All novel products, processes and uses substantiallyas herein described with particular reference to the Examples.